MedWorm.com provides a medical RSS filtering service. Over 6000 RSS medical sources are combined and output via different filters. This feed contains the latest items from the 'Current Topics in Medicinal Chemistry' source. Thu, 09 Feb 2012 13:01:35 +0100 http://www.medworm.com/index.php?rid=5577759&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22204480%26dopt%3DAbstract Authors: Taliani S, Da Settimo F PMID: 22204480 [PubMed - as supplied by publisher] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5577759 Tue, 10 Jan 2012 19:56:11 +0100 5577759 http://www.medworm.com/index.php?rid=5577758&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22204481%26dopt%3DAbstract Authors: Costa B, Pozzo ED, Martini C Abstract Neurosteroids are able to rapidly control the excitability of the central nervous system, acting as regulators of type A receptors for GABA. Over the last two decades, many authors have confirmed that neurosteroid level alterations occur in psychiatric disorders, including anxiety disorders. More recently, investigators have manipulated neurosteroidogenesis in an effort to correct neuronal excitation and inhibition imbalances, which may lie at the root of neuropsychiatric conditions. In line with this strategy, emerging data have demonstrated that a promising target for therapy of anxiety disorders is the Translocator Protein (TSPO). TSPO is a five transmembrane domain protein (18 kDa) that is expressed predominantly in steroid-synthes... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5577758 Tue, 10 Jan 2012 19:55:59 +0100 5577758 http://www.medworm.com/index.php?rid=5577757&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22204482%26dopt%3DAbstract Authors: Cosimelli B, Cosconati S, Marinelli L, Novellino E, Greco G Abstract Interaction between the so-called benzodiazepine receptor (BzR) and the chemically heterogeneous class of its ligands is still one of the most challenging objects of theoretical studies. In the mid-90s our group began to collaborate with Prof. Antonio Da Settimo and coworkers to a project of synthesis and biological evaluation of indolylglyoxylamides designed as BzR ligands. Herein we review our efforts in designing these compounds and in interpreting their structure-affinity relationships. Our investigations were carried out for years by adopting the pharmacophore/topological model for BzR ligands set up by Cook's group. In an attempt to rationalize some puzzling structure-affinity relationships we specu... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5577757 Tue, 10 Jan 2012 19:55:48 +0100 5577757 http://www.medworm.com/index.php?rid=5577756&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22204483%26dopt%3DAbstract Authors: Marazziti D, Carlini M, Dell'osso L Abstract Anxiety disorders represent the most prevalent psychiatric disorders. In addition, a considerable burden is associated with them, not only for individual sufferers, but also for the health care system. However, many patients who might benefit from treatment are not diagnosed or treated. This may partly be due to lack of awareness of the anxiety disorders by primary care practitioners and by the sufferers themselves. In addition, the stigma still associated with psychiatric disorders and lack of confidence in psychiatric treatments are factors leading to no/under recognition and treatment, or the use of unnecessary or inappropriate treatments. This paper aims to provide a comprehensive review of recommendations for the pharmacolo... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5577756 Tue, 10 Jan 2012 19:55:37 +0100 5577756 http://www.medworm.com/index.php?rid=5577755&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22204484%26dopt%3DAbstract Authors: Salerno S, Da Settimo F, Taliani S, Simorini F, La Motta C, Fornaciari G, Marini AM Abstract The classical benzodiazepines (Bz) constitute a well-known class of therapeutics displaying hypnotic, anxiolytic and anticonvulsant effects acting upon a specific binding site (BzR) belonging to the GABAA receptor complex. Their usefulness, however, is limited by a broad range of side effects; consequently the fact that the action of GABA with the receptor complex could be allosterically modulated by a wide variety of chemical entities, made the Bz binding site, from late eighties to nowdays, the target of extensive research programmes directed to the identification of new ligands displaying varying degrees of affinity- and efficacy-selectivity for the different GABAA/BzR-subtypes.... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5577755 Tue, 10 Jan 2012 19:55:25 +0100 5577755 http://www.medworm.com/index.php?rid=5577754&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22204485%26dopt%3DAbstract Authors: Ortore G, Tuccinardi T, Martinelli A Abstract The Translocator Protein (18 kDa) (TSPO), previously known as the peripheral benzodiazepine receptor, is widely expressed in glial cells and in peripheral tissues and is involved in a variety of biological processes: steroidogenesis, cell growth and differentiation, apoptosis induction, etc. TSPO basal expression is up-regulated in a number of human pathologies, including a variety of tumors and neuropathologies, such as gliomas and neurodegenerative disorders (Huntington's and Alzheimer's diseases), as well as in various forms of brain injury and inflammation. Furthermore, changes in TSPO receptor levels have been found in anxiety and mood disorders. Nowadays, considerable efforts have been focused on the identification of new... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5577754 Tue, 10 Jan 2012 19:55:13 +0100 5577754 http://www.medworm.com/index.php?rid=5577753&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22204486%26dopt%3DAbstract Authors: Nothdurfter C, Rupprecht R, Rammes G Abstract Anxiety disorders are frequent and disabling disorders. For short-term treatment, benzodiazepines are useful due to their rapid onset of anxiolytic action. However, these compounds have sedative properties and may induce tolerance, abuse liability and withdrawal symptoms. First-line choices for the long-term treatment are selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors. The major disadvantage of these compounds is their delayed onset of action. It is obvious that there is a need for novel pharmacological approaches that combine a rapid anxiolytic efficacy with the lack of tolerance induction, abuse liability and withdrawal symptoms. A very important target for the development of such comp... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5577753 Tue, 10 Jan 2012 19:54:59 +0100 5577753 http://www.medworm.com/index.php?rid=5577752&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22204487%26dopt%3DAbstract Authors: Simorini F, Marini AM, Taliani S, La Motta C, Salerno S, Pugliesi I, Da Settimo F Abstract The mitochondrial translocator protein (TSPO) mediates the synthesis of neurosteroids in the CNS, which have been demonstrated to enhance the neurotransmitter GABA response, exhibiting related behavioural properties. Selective TSPO ligands are able to stimulate steroidogenesis with great efficacy, thus representing potential anxiolytic agents. This review describes the development of a class of high affinity ligands to TSPO, N,N-dialkylindol-3-ylglyoxylamides (IGA), from the initial stages of design to the pharmacological characterization of selected compounds for their anxiolytic activity. Affinity data and SARs of the new class of ligands are discussed; the potential applications o... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5577752 Tue, 10 Jan 2012 19:54:46 +0100 5577752 http://www.medworm.com/index.php?rid=5577751&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22204488%26dopt%3DAbstract Authors: Trincavelli ML, Pozzob ED, Daniele S, Martini C Abstract Anxiety disorders have been linked to alterations in γ-aminobutyric acid (GABA) neurotransmission. GABA interacts with the ligand-gated ion channels, GABAA receptor (GABAA-R) subtypes, and regulates the flow of chloride into the cell, causing neuron hyperpolarization. GABAA-Rs are assembled from a family of 19 homologous subunit gene products and form mostly hetero-oligomeric pentamers. The major isoforms of the GABAA-Rs contain α, β and γ subunits and show a regional heterogeneity that is associated with distinct physiological effects. A variety of allosteric ligands can modulate the response to GABA by binding at different sites on the GABAA-R complex. The best-characterized binding site is the benzodiazepine (... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5577751 Tue, 10 Jan 2012 19:54:31 +0100 5577751 http://www.medworm.com/index.php?rid=5577750&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22204489%26dopt%3DAbstract Authors: Sartini S, Morelli M, Simorini F, Taliani S, Salerno S, Marini AM, Da Settimo F, La Motta C Abstract Indolylglyoxylamides are a class of distinctive benzodiazepine receptor ligands, proposed in the mid-eighties as open analogues of β-carbolines. Thorough and long-lasting studies of their structure-activity relationships led to the development of a great deal of derivatives, to satisfy increasingly structural and pharmacophoric requirements of the benzodiazepine binding site in the central nervous system. Efforts to pre-organize their flexible structure in the three-dimensional shape adopted when bound to the receptor led to the identification of two novel classes of rigid ligands, characterized by planar tricyclic heteroaromatic cores: the [1,2,4]triazino[4,3-a]benzimidaz... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5577750 Tue, 10 Jan 2012 19:54:16 +0100 5577750 http://www.medworm.com/index.php?rid=5548084&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22196272%26dopt%3DAbstract Authors: Lens M PMID: 22196272 [PubMed - as supplied by publisher] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5548084 Thu, 29 Dec 2011 03:49:13 +0100 5548084 http://www.medworm.com/index.php?rid=5548083&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22196273%26dopt%3DAbstract Authors: Schiffelers RM PMID: 22196273 [PubMed - as supplied by publisher] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5548083 Thu, 29 Dec 2011 03:49:03 +0100 5548083 http://www.medworm.com/index.php?rid=5548082&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22196274%26dopt%3DAbstract Authors: Foged C Abstract A key hurdle for the further development of RNA interference (RNAi) therapeutics is their safe and effective delivery. Lipids are promising and versatile carriers since they are based on Nature´s own building blocks and can be provided with properties which allow for siRNA protection, steric stabilization, targeting, membrane fusion and triggerable drug release. At present a variety of lipid-based transfectants for small interfering RNA (siRNA) delivery have been used for in vitro and in vivo studies. The majority bear a cationic charge to electrostatically complex the siRNA into lipoplexes. The hydrophobization of the siRNA by the lipids promotes passage across cellular membrane barriers, especially when lipids are added that facilitate membrane fusion. ... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5548082 Thu, 29 Dec 2011 03:48:53 +0100 5548082 http://www.medworm.com/index.php?rid=5548081&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22196275%26dopt%3DAbstract Authors: Naeye B, Raemdonck K, Remaut K, Demeester J, De Smedt SC Abstract Over the last decade, considerable effort has been put in the implementation of RNA interference (RNAi) as a treatment for various disorders. As RNAi occurs in the cytoplasm of cells, it is imperative that RNAi mediators such as small interfering RNA (siRNA) cross several extracellular and intracellular barriers to reach this site of action. Among the extensive range of proposed delivery systems for siRNA, matrix systems possess interesting properties to promote the delivery of siRNA to a target tissue. In this review, a number of recently developed matrix and hybrid systems for siRNA delivery are discussed. PMID: 22196275 [PubMed - as supplied by publisher] (Source: Current Topics in Medicinal Chemistry... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5548081 Thu, 29 Dec 2011 03:48:43 +0100 5548081 http://www.medworm.com/index.php?rid=5548080&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22196276%26dopt%3DAbstract Authors: Ohrt T, Muetze J, Svoboda P, Schwille P Abstract Several different pathways, generally termed RNA silencing pathways, utilize small RNA molecules guiding sequence-specific silencing effects of ribonucleoprotein effector complexes, traditionally termed RNA-induced silencing complex (RISC). Three RNA silencing pathways were recognized in mammalian cells: RNA interference (RNAi), where short RNAs produced from long double-stranded RNA guide cleavage of cognate mRNAs, microRNA (miRNA) pathway, where endogenously-encoded miRNAs typically induce translational repression, and piRNA pathway, where piRNAs (PIWI-associated RNAs) guide repression of repetitive sequences in the germline. Originally, RNAi and miRNA pathways were thought to act in the cytoplasm, however, there is a grow... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5548080 Thu, 29 Dec 2011 03:48:32 +0100 5548080 http://www.medworm.com/index.php?rid=5548079&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22196277%26dopt%3DAbstract Authors: Pennati M, Millo E, Gandellini P, Folini M, Zaffaroni N Abstract The ability to evade apoptosis is one of the defining hallmarks of cancer. It enables the survival of cancer cells under abnormal growth stimulation and mediates their increased resistance to treatment with cytotoxic drugs and radiation. Therefore, antiapoptotic proteins that counteract apoptosis signaling represent promising new therapeutic targets to impair cancer cell growth and enhance treatment response. As soon as RNA interference (RNAi) was demonstrated in mammalian cells, it rapidly became an essential tool for gene knockdown in preclinical models, making it possible to define the role of specific genes in the onset and progression of cancer and explore their potential as therapeutic targets. The pres... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5548079 Thu, 29 Dec 2011 03:48:22 +0100 5548079 http://www.medworm.com/index.php?rid=5548078&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22196278%26dopt%3DAbstract Authors: Vader P, van der Aa LJ, Storm G, Schiffelers RM, Engbersen JJ Abstract RNA interference is a technique to induce sequence-specific gene silencing, but is hampered by inefficient delivery of its mediator, short interfering RNA, into target cells. This review describes recent advances in siRNA delivery using polymeric carrier systems. Structural variations that have been applied to these polymers for optimizing their intracellular trafficking are discussed, as well as strategies for stabilization and targeting to diseased tissues in vivo. Recent findings have highlighted safety issues that need to be taken into account in the design of nanoparticles for clinical application. PMID: 22196278 [PubMed - as supplied by publisher] (Source: Current Topics in Medicinal Chemistry... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5548078 Thu, 29 Dec 2011 03:48:12 +0100 5548078 http://www.medworm.com/index.php?rid=5379089&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22044224%26dopt%3DAbstract Authors: Gochin M PMID: 22044224 [PubMed - as supplied by publisher] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5379089 Fri, 28 Oct 2011 04:00:00 +0100 5379089 http://www.medworm.com/index.php?rid=5379088&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22044225%26dopt%3DAbstract Authors: Garg H, Viard M, Jacobs A, Blumenthal R Abstract HIV gp41 is a metastable protein whose native conformation is maintained in the form of a heterodimer with gp120. The non-covalently associated gp41/gp120 complex forms a trimer on the virus surface. As gp120 engages with HIV's receptor, CD4, and coreceptor, CXCR4 or CCR5, gp41 undergoes several conformational changes resulting in fusion between the viral and cellular membranes. Several lipophilic and amphiphilic domains have been shown to be critical in that process. While the obvious function of gp41 in viral entry is well-established its role in cellular membrane fusion and the link with pathogenesis are only now beginning to appear. Recent targeting of gp41 via fusion inhibitors has revealed an important role of this pro... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5379088 Fri, 28 Oct 2011 04:00:00 +0100 5379088 http://www.medworm.com/index.php?rid=5379087&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22044226%26dopt%3DAbstract Authors: Gochin M, Zhou G Abstract Small molecule inhibition of HIV fusion has been an elusive goal, despite years of effort by both pharmaceutical and academic laboratories. In this review, we will discuss the amphipathic properties of both peptide and small molecule inhibitors of gp41-mediated fusion. Many of the peptides and small molecules that have been developed target a large hydrophobic pocket situated within the grooves of the coiled coil, a potential hotspot for inhibiting the trimer of hairpin formation that accompanies fusion. Peptide studies reveal molecular properties required for effective inhibition, including elongated structure and lipophilic or amphiphilic nature. The characteristics of peptides that bind in this pocket provide features that should be considered... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5379087 Fri, 28 Oct 2011 04:00:00 +0100 5379087 http://www.medworm.com/index.php?rid=5379086&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22044227%26dopt%3DAbstract Authors: Huarte N, Lorizate M, Pérez-Payá E, Nieva JL Abstract The fusogenic function of HIV-1 gp41 transmembrane Env subunit relies on two different kinds of structural elements: i) a collapsible ectodomain structure (the hairpin or six-helix bundle) that opens and closes, and ii) two membrane-transferring regions (MTRs), the fusion peptide (FP) and the membrane-proximal external region (MPER), which ensure coupling of hairpin closure to apposition and fusion of cell and viral membranes. The isolation of naturally produced short peptides and neutralizing IgG-s, that interact with FP and MPER, respectively, and block viral infection, suggests that these conserved regions might represent useful targets for clinical intervention. Furthermore, MTR-derived peptides have been shown to... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5379086 Fri, 28 Oct 2011 04:00:00 +0100 5379086 http://www.medworm.com/index.php?rid=5379085&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22044228%26dopt%3DAbstract Authors: Gach JS, Leaman DP, Zwick MB Abstract HIV-1 envelope glycoprotein (Env) spikes are supported at the viral membrane interface by a highly conserved and hydrophobicregionof gp41, designated the membrane-proximal external region (MPER). The MPER is mandatory for infection of host cells by HIV-1, and is the target of some of the most broadly neutralizing antibodies described to date. As such, the MPER is also of considerable interest for HIV vaccine design. However, structural models indicate that the MPER assumes distinct conformations prior to and leading up toEnv-mediated fusion. Thus, the more of these distinct conformations that antibodies and inhibitors can recognize will likely bethe betterfor antiviral potency. In addition to its flexibility, the MPER is lipophilicand ... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5379085 Fri, 28 Oct 2011 04:00:00 +0100 5379085 http://www.medworm.com/index.php?rid=5379084&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22044229%26dopt%3DAbstract Authors: Cai L, Gochin M, Liu K Abstract Human immunodeficiency virus type 1 (HIV-1), the pathogen of acquired immunodeficiency syndrome (AIDS), causes ~2 millions death every year and still defies an effective vaccine. HIV-1 infects host cells through envelope protein - mediated virus-cell fusion. The transmembrane subunit of envelope protein, gp41, is the molecular machinery which facilitates fusion. Its ectodomain contains several distinguishing functional domains, fusion peptide (FP), N-terminal heptad repeat (NHR), C-terminal heptad repeat (CHR) and membrane proximal extracellular region (MPER). During the fusion process, FP inserts into the host cell membrane, and an extended gp41 prehairpin conformation bridges the viral and cell membranes through MPER and FP respectively. S... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5379084 Fri, 28 Oct 2011 04:00:00 +0100 5379084 http://www.medworm.com/index.php?rid=5379098&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22039874%26dopt%3DAbstract Authors: Marco-Contelles J, Soriano E PMID: 22039874 [PubMed - as supplied by publisher] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5379098 Thu, 27 Oct 2011 04:00:00 +0100 5379098 http://www.medworm.com/index.php?rid=5379097&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22039875%26dopt%3DAbstract Authors: Rampa A, Belluti F, Gobbi S, Bisi A Abstract Progresses in medicinal chemistry over the last few years have focused on the design and synthesis of hybrid compounds, molecules encompassing in a single scaffold two pharmacophores from known entities endowed with well established biological activities. The interest in this topic is related to the increasing emphasis on the identification of the different factors involved in a number of disorders, such as the complex multifactorial Alzheimer's disease (AD), and hybrid-based strategy has become a focal point in this medicinal chemistry field since it could lead to derivatives with an improved biological profile. Using this strategy, acetylcholinesterase inhibitors (AChEIs) have been extensively coupled with properly selected bi... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5379097 Thu, 27 Oct 2011 04:00:00 +0100 5379097 http://www.medworm.com/index.php?rid=5379096&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22039876%26dopt%3DAbstract Authors: Elsinghorst PW, Härtig W, Gündisch D, Mohr K, Tränkle C, Gütschow M Abstract The occurrence of orthosteric and allosteric binding sites is a characteristic common feature of several acetylcholine-binding proteins, like acetylcholinesterase or the nicotinic and muscarinic acetylcholine receptors. These proteins are involved in a number of neurological disorders, such as Alzheimer's disease, and represent important therapeutic targets for the development of heterodimeric ligands addressing both of their binding sites. Among the pharmacophores, which have been combined in such heterodimers, the tetrahydroacridine derivative tacrine has attracted particular interest. This review discusses the chemistry behind the linker connection of tacrine to other pharmacophores and sum... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5379096 Thu, 27 Oct 2011 04:00:00 +0100 5379096 http://www.medworm.com/index.php?rid=5379095&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22039877%26dopt%3DAbstract Authors: Alvarez R, Altucci L, Gronemeyer H, de Lera AR Abstract The development of ligands that as single chemical entities are able to modulate multiple epigenetic targets simultaneously (designed epigenetic multiple ligands) is still in its infancy. We are witnessing some advances with combinations of the fused or linked pharmacophores of an epi-drug and other anticancer agents. More recently, however, a very promising approach has been developed in which a single chemical entity exerts several therapeutic activities simultaneously, such as a compound that inhibits several epigenetic enzymes and as a consequence display multiple biological profiles that address synergistically a particular multifactorial disease. Despite their promiscuity, these multiple epigenetic ligands have ... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5379095 Thu, 27 Oct 2011 04:00:00 +0100 5379095 http://www.medworm.com/index.php?rid=5379094&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22039878%26dopt%3DAbstract Authors: Binda C, Milczek EM, Bonivento D, Wang J, Mattevi A, Edmondson DE Abstract Playing a pivotal role in the metabolism of neurotransmitters in the central nervous system, the mitochondrial enzymes monoamine oxidases A and B (MAO A and B) have been for long studied as drug targets for neurodegenerative and neurological diseases. MAO inhibitors (MAOIs) are clinically used to treat Parkinson's disease and depression by blocking the degradation of neuroactive catecholamines and providing a symptomatic relief in the patients. More recent is the idea that the neuroprotective effect of MAOIs may result from the prevention of oxidative stress produced by the MAO reaction rather than being simply related to the inhibition of neurotransmitters degradation. Tranylcypromine and phenelzin... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5379094 Thu, 27 Oct 2011 04:00:00 +0100 5379094 http://www.medworm.com/index.php?rid=5379093&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22039879%26dopt%3DAbstract Authors: Bolognesi ML, Simoni E, Rosini M, Minarini A, Tumiatti V, Melchiorre C Abstract Multitarget agents directed at selected molecular targets involved in the pathogenic cascade of Alzheimer's disease (AD) have been increasingly sought after in recent years, with the aim of achieving enhanced therapeutic efficiency with respect to single-target drugs and drug candidates. At the same time, much attention has been devoted to identifying high quality pharmacological tools to help explore the molecular mechanisms underlying AD without being exposed to physicochemical challenges. Herein, we discuss several examples of both types of compounds, taken from our own research and derived from the leads memoquin, lipocrine and bis(7)tacrine. PMID: 22039879 [PubMed - as supplied by publ... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5379093 Thu, 27 Oct 2011 04:00:00 +0100 5379093 http://www.medworm.com/index.php?rid=5379092&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22039880%26dopt%3DAbstract Authors: Bolognesi ML Abstract Of the tropical diseases, trypanosomiases and leishmaniases should most concern the pharmaceutical community because of their high prevalence in developing countries and the lack of effective drug treatments. Despite this, they have not historically received much attention in terms of investment and research effort, nor do they now. In very recent years, thanks to the involvement of several nonprofit organizations, the chemotherapeutic options have expanded with the introduction of the first combination therapy. The optimal efficacy and safety of nifurtimox-eflornithine combination against second-stage human African trypanosomiasis is an encouraging first step towards simpler and more affordable therapies. Along the same line, I propose that single ch... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5379092 Thu, 27 Oct 2011 04:00:00 +0100 5379092 http://www.medworm.com/index.php?rid=5379091&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22039881%26dopt%3DAbstract Authors: Egea J, Rios CD Abstract The synthesis and the pharmacological evaluation of 1,8-naphthyridine derivatives and related compounds as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as voltage-dependant Ca(2+) channels (VDCC) modulators of are summarized. These compounds are closely related to the anticholinesterasic tacrine and the well-known Ca(2+)-antagonists 1,4-dihydropyridines. They were obtained from polyfunctionalized 2-amino-3-cyano-heterocycles via Friedlander-type reaction with selected cycloalkanones. Most of the compounds showed moderate inhibitory activity of cholinesterases, with selectivity to the AChE inhibition, and blocked Ca(2+) channels, preferentially the L-subtype, when a 4-aryl-1,4-DHP-like moiety were present in i... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5379091 Thu, 27 Oct 2011 04:00:00 +0100 5379091 http://www.medworm.com/index.php?rid=5379090&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22039882%26dopt%3DAbstract Authors: Ilić M, Kikelj D, Ilaš J Abstract Thromboembolic disorders are still the leading causes of morbidity and mortality in developed societies. Therefore, prophylaxis and treatment of arterial and venous thrombosis are among the main therapeutic challenges nowadays. Simultaneous action on several targets involved in pathology of thrombosis offers potential advantages compared to existing drugs which were developed as selective modulators of single targets. The review focuses on dual inhibitors of coagulation enzymes, dual antiaggregatory compounds exerting their action on different combinations of platelet targets, as well as on anticoagulant/antiaggregatory compounds which interfere with at least one target involved in blood coagulation and at least one target engaged in the... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5379090 Thu, 27 Oct 2011 04:00:00 +0100 5379090 http://www.medworm.com/index.php?rid=5379107&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22039865%26dopt%3DAbstract Authors: Nazarov AA, Hartinger CG PMID: 22039865 [PubMed - as supplied by publisher] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5379107 Thu, 20 Oct 2011 04:00:00 +0100 5379107 http://www.medworm.com/index.php?rid=5379106&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22039866%26dopt%3DAbstract Authors: Casini A, Luigi M Abstract Nowadays, gold compounds constitute a family of very promising experimental agents for cancer treatment. Indeed, several gold(I) and gold(III) compounds were shown to manifest outstanding antiproliferative properties in vitro against selected human tumor cell lines and some of them performed remarkably well even in tumor models in vivo. Notably, the peculiar chemical properties of the gold centre impart innovative pharmacological profiles to gold-based metallodrugs most likely in relation to novel molecular mechanisms. The precise mechanisms through which cytotoxic gold compounds produce their biological effects are still largely unknown. Within this frame, the major aim of this review is to define the possible modes of action and the most probab... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5379106 Thu, 20 Oct 2011 04:00:00 +0100 5379106 http://www.medworm.com/index.php?rid=5379105&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22039867%26dopt%3DAbstract Authors: Farrell NP Abstract This review summarizes clinical and pre-clinical results on platinum anti-cancer drug formulations. A concise summary of the use of oxidation state to modulate cancer pharmacology is given for Pt(IV) complexes, distinct from the clinically used Pt(II) drugs. The chemistry of platinum drug formulation combines aspects of kinetics of active moiety release from nominally weak-binding ligands (bond cleavage from platinum-carboxylate and platinum-phosphate) in polymers and nanoparticles with pharmacological considerations of plasma distribution and cellular accumulation. The action of any molecular entity as a drug is influenced by its ADME profile - absorption, distribution, metabolism and excretion. The purpose of drug formulation is to alter any or all of... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5379105 Thu, 20 Oct 2011 04:00:00 +0100 5379105 http://www.medworm.com/index.php?rid=5379104&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22039868%26dopt%3DAbstract Authors: Groessl M, Dyson PJ Abstract Platinum-based drugs present one of the pillars of anticancer chemotherapy, and pharmaceuticals incorporating metals such as ruthenium, gallium, titanium and gold, some of which have already entered clinical trials, show promising features including activity against platinum-resistant tumors and/or reduced side-effects. The mode of action of these novel metallodrugs has only been partly elucidated, and even for established treatments, some questions concerning the interactions with targets such as DNA and proteins on a molecular level remain unanswered. In order to tackle the challenging problem of characterizing the behavior of metallodrugs in complex biological media and tissues in vitro and in vivo, bioanalytical and biophysical methodologie... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5379104 Thu, 20 Oct 2011 04:00:00 +0100 5379104 http://www.medworm.com/index.php?rid=5379103&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22039869%26dopt%3DAbstract Authors: Ang WH, Jothibasu R, Ma M Abstract Over the past four decades, the search for improved platinum drugs based on the classical platinum(II)-diam(m)ine pharmacophore has yielded only a handful of successful candidates. New methodologies centred on platinum(IV) complexes, with better stability and expanded coordination spheres, offer the possibility of overcoming limitations inherent to platinum(II) drugs. In this review, novel strategies of targeting and killing cancer cells using platinum(IV) constructs are discussed. These approaches exploit the unique electrochemical characteristics and structural attributes of platinum(IV) complexes as a means of developing anticancer prodrugs that can target and selectively destroy cancer cells. Anticancer platinum(IV) prodrugs represent... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5379103 Thu, 20 Oct 2011 04:00:00 +0100 5379103 http://www.medworm.com/index.php?rid=5379102&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22039870%26dopt%3DAbstract Authors: Milaeva ER Abstract The oxidative stress that is associated with the abnormal level of reactive oxygen species (ROS) is considered to be involved in the carcinogenesis process. The antioxidative defense system in the living organism regulates the toxic impact of ROS and there is strong evidence that the antioxidants prevent carcinogenesis. This review will focus on a novel approach to design synthetic metal-based antioxidants and to study their in vitro, ex vivo and in vivo activities in the cellular oxidation processes that might be involved in promotion of carcinogenesis. The antioxidants are divided into several groups depending on the nature of the ligands used: 2,6-dialkylphenols, flavonoids, polyphenols, peptides, purines, pyridines and their derivatives. Some curren... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5379102 Thu, 20 Oct 2011 04:00:00 +0100 5379102 http://www.medworm.com/index.php?rid=5379101&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22039871%26dopt%3DAbstract Authors: Hartinger CG, Andrew D P, Alexey A N Abstract Polynuclear compounds are a relatively new and successful approach in metal-based cancer chemotherapy as typified by the trinuclear Pt compound BBR3464 which was evaluated in clinical trials. In this review, we discuss newer developments of multinuclear ruthenium, osmium and gold complexes with more than one metal center, focusing on their anticancer activity. The compounds presented are often supposed to exert their anticancer activity by different modes of action as compared to established drugs, including newly proposed mechanisms such as enzyme inhibition, crosslinking of biomacromolecules or through photo-activation, though many of the examples are also capable of binding to DNA nucleobases. Important metabolization and ch... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5379101 Thu, 20 Oct 2011 04:00:00 +0100 5379101 http://www.medworm.com/index.php?rid=5379100&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22039872%26dopt%3DAbstract Authors: Quiroga AG Abstract The potential and limitations of the non classical metallodrugs with platinum as metal are discussed in this section, focusing not only in their design but in their mechanism of action and interaction with other biomolecules to introduce and encourage the readers on the potential of this field. PMID: 22039872 [PubMed - as supplied by publisher] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5379100 Thu, 20 Oct 2011 04:00:00 +0100 5379100 http://www.medworm.com/index.php?rid=5379099&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22039873%26dopt%3DAbstract Authors: Iztok T, Jakob K Abstract In this review several types of interactions between metal ions and DNA are given, starting from basic binding to the use of metal complexes in cancer treatment and diagnostics. Metal cations help to neutralize the negative charge of DNA and thus enable the normal functions of DNA but many other interactions are also possible and are discussed in this paper. Various consequences of such interactions can be reversible (e. g. conformational changes) or irreversible (e. g. cleavage). It is known that some metal ions can also damage DNA which can provoke mutations and in some cases leads to cancer. It is clear that we know a lot about metal-DNA interactions but much more information is needed to understand the role of metal ions completely and to use ... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5379099 Thu, 20 Oct 2011 04:00:00 +0100 5379099 http://www.medworm.com/index.php?rid=5174820&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21851335%26dopt%3DAbstract Authors: Briansó F, Carrascosa MC, Oprea TI, Mestres J Abstract The degree of applicability of chemogenomic approaches to protein families depends on the accuracy and completeness of pharmacological data and the corresponding level of pharmacological similarity observed among their protein members. The recent public domain availability of pharmacological data for thousands of small molecules on 204 G protein-coupled receptors (GPCRs) provides a firm basis for an in-depth cross-pharmacology analysis of this superfamily. The number of protein targets included in the cross-pharmacology profile of the different GPCRs changes significantly upon varying the ligand similarity and binding affinity criteria. However, with the exception of muscarinic receptors, aminergic GPCRs distinguish t... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5174820 Tue, 30 Aug 2011 06:16:02 +0100 5174820 http://www.medworm.com/index.php?rid=5140988&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21824106%26dopt%3DAbstract Authors: Lei M, Zhu Y Abstract The target proteasome has been the focus of drug discovery since the first drug bortezomib was launched in 2003. Many structurally diverse proteasome inhibitors were discovered and even some of them entered the clinical trials. Due to rapid technological progress in chemistry, bioinformatics, structural biology and computer technology, computer-aided drug design (CADD) plays more and more important role in today's drug discovery. Many CADD technologies were employed in designing various inhibitors of proteasome in the past years. This review gives a global description of the development of computer-aided proteasome inhibitor design by using different commercial or academic software. The binding modes of some structurally novel inhibitors with proteaso... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5140988 Mon, 08 Aug 2011 23:00:00 +0100 5140988 http://www.medworm.com/index.php?rid=5140987&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21824107%26dopt%3DAbstract Authors: Lee W, Kim KB Abstract The proteasome, a large multisubunit protease complex, has been extensively investigated over the years, greatly enhancing our understanding of critical roles that the proteasome plays in cells. The FDA approval of bortezomib for the treatment of multiple myeloma and mantle cell lymphoma has validated the proteasome as an anticancer target. However, the undesirable toxicities of these agents limit their broad utility. The immunoproteasome, an alternative form of the constitutive proteasome, has recently been explored as a therapeutic target. While the immunoproteasome, normally expressed in cells of hematopoietic origin, has been shown to be associated with various types of cancer and inflammatory diseases, its multifaceted function is not fully unde... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5140987 Mon, 08 Aug 2011 23:00:00 +0100 5140987 http://www.medworm.com/index.php?rid=5140986&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21824108%26dopt%3DAbstract Authors: Ma Y, Qu L, Liu Z, Zhang L, Yang Z, Zhan L Abstract Salinosporamide A (4), a secondary metabolite of the marine actinomycete Salinispora tropica, is a potent inhibitor of 20S proteasome that is currently in clinical trials for the treatment of cancers. Herein, we described various synthetic strategies of 4 and summarized the SAR of 4 and its analogs. PMID: 21824108 [PubMed - as supplied by publisher] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5140986 Mon, 08 Aug 2011 23:00:00 +0100 5140986 http://www.medworm.com/index.php?rid=5140985&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21824109%26dopt%3DAbstract Authors: Frezza M, Schmitt S, Dou QP Abstract Selective degradation of proteins by the ubiquitin-proteasome pathway is a critical determinant for maintaining cellular homeostasis. Most intracellular proteins are degraded by the proteasome, a multicatalytic enzyme complex containing a 20S catalytic core and two 19S regulatory complexes. Many proteasome target proteins are involved in the regulation of important processes of carcinogenesis and cancer cell survival, such as cell cycle progression, cell proliferation, differentiation and apoptosis. Indeed, the ubiquitin-proteasome-dependent degradation pathway plays an essential role in both the up-regulation of cell proliferation and down-regulation of cell death in human cancer cells. Both in vitro and in vivo experimental and clinic... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5140985 Mon, 08 Aug 2011 23:00:00 +0100 5140985 http://www.medworm.com/index.php?rid=5140984&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21824110%26dopt%3DAbstract Authors: Ding F, Yin Z, Wang HR Abstract The Rho family small GTPases of the Ras superfamily play key roles in regulating diverse signaling pathways that control a myriad of fundamental cellular processes such as cytoskeletal dynamics, cell cycle progression, gene expression, cell polarity, migration and cell transformation. The Rho GTPases cycle between an active GTP-bound and an inactive GDP-bound form, which is controlled by many regulators including GEFs, GAPs and GDIs. Recent studies have revealed a new layer of regulation for Rho GTPases, indicating that several members of the Rho family of small GTPases including RhoA, Rac1, and RhoBTB, as well as the Ras family member Rap1B, are also regulated by the ubiquitin-proteasome pathway, which plays important roles in controlling c... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5140984 Mon, 08 Aug 2011 23:00:00 +0100 5140984 http://www.medworm.com/index.php?rid=5140983&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21824111%26dopt%3DAbstract Authors: Groll M, Potts BC Abstract The 26S proteasome is the enzymatic core engine of the ubiquitin and proteasome dependent proteolytic system (UPS), the major eukaryotic pathway for regulated protein degradation. The UPS plays a pivotal role in cellular protein turnover, protein quality control, antigen processing, signal transduction, cell cycle regulation, cell differentiation and apoptosis, inspiring in-depth studies of proteasome structure and function and the search for selective inhibitors. Structural studies revealed that the 26S proteasome comprises up to two 19S regulatory caps flanking a cylindrical 20S core particle, which houses the proteolytic subunits and is present in all kingdoms of life. This review highlights current understanding of 20S architecture, maturatio... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5140983 Mon, 08 Aug 2011 23:00:00 +0100 5140983 http://www.medworm.com/index.php?rid=5140982&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21824112%26dopt%3DAbstract Authors: Zhu Y PMID: 21824112 [PubMed - as supplied by publisher] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5140982 Mon, 08 Aug 2011 23:00:00 +0100 5140982 http://www.medworm.com/index.php?rid=5000822&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21726190%26dopt%3DAbstract Authors: Briansó F, Carrascosa MC, Oprea TI, Mestres J The degree of applicability of chemogenomic approaches to protein families depends on the accuracy and completeness of pharmacological data and the corresponding level of pharmacological similarity observed among their protein members. The recent public domain availability of pharmacological data for thousands of small molecules on 204 G protein-coupled receptors (GPCRs) provides a firm basis for an in-depth cross-pharmacology analysis of this superfamily. The number of protein targets included in the cross-pharmacology profile of the different GPCRs changes significantly upon varying the ligand similarity and binding affinity criteria. However, with the exception of muscarinic receptors, aminergic GPCRs distinguish themselves fro... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5000822 Sun, 03 Jul 2011 23:00:00 +0100 5000822 http://www.medworm.com/index.php?rid=5000823&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21699494%26dopt%3DAbstract Authors: Girish KS, Kemparaju K Snakebite is a medical emergency in many parts of the world, particularly in the temperate regions. According to 2007 World Health Organization (WHO) report, there are about 5 million snakebite incidences resulting in 2.5 million envenoming, and 125,000 deaths occur annually. Most affected are the healthy individuals like children and farming populations with resource poor settings and away from health care centers in low-income countries of Africa, Asia and Latin America. In view of this, the WHO has declared snakebite as an ignored health crisis and a tropical disease. Although the death rate has reduced markedly due to anti-venom regiment, several limitations of it offer scope for better understanding of various ignored issues. Currently, snakebite th... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=5000823 Wed, 22 Jun 2011 23:00:00 +0100 5000823 http://www.medworm.com/index.php?rid=4955047&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21682678%26dopt%3DAbstract Authors: Sunitha K, Hemshekhar M, Santhosh MS, Kumar MS, Kemparaju K, Girish KS The mortality rate due to snakebite is reduced markedly by the use of anti-venoms, which are the only medically approved remedial agents available. The anti-venoms effectively neutralize the systemic toxicity but offer no protection towards local tissue degradation. In viperid snake envenomations, SVMPs and SVHYs are the major agents responsible for brutal local tissue damage as they degrade ECM and basement membrane surrounding the blood vessels. Thus, the usage of inhibitor(s) against ECM degrading enzymes in the treatment of viper bites is an affirmative therapeutic choice. The present study assessed the efficacy of N-acetyl cysteine (NAC) to inhibit gelatinase, hyaluronidase, hemorrhagic and defibrinoge... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4955047 Thu, 16 Jun 2011 23:00:00 +0100 4955047 http://www.medworm.com/index.php?rid=4955046&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21682679%26dopt%3DAbstract Authors: Raghavendra Gowda CD, Shivaprasad HV, Kumar RV, Rajesh R, Saikumari YK, Frey BM, Frey FJ, Sharath BK, Vishwanath BS A major myonecrotic zinc containing metalloprotease 'malabarin' with thrombin like activity was purified by the combination of gel permeation and anion exchange chromatography from T. malabaricus snake venom. MALDI-TOF analysis of malabarin was gave a molecular mass of 45.76 kDa and its N-terminal sequence was found to be Ile-Ile-Leu-Pro(Leu)-Ile-Gly-Val-Ile-Leu(Glu)-Thr-Thr. Atomic absorption spectral analysis of malabarin raveled the association of zinc metal ion. Malabarin is not lethal when injected i.p. or i.m. but causes extensive hemorrhage and degradation of muscle tissue within 24 hours. Sections of muscle tissue under light microscope revealed hemorrhag... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4955046 Thu, 16 Jun 2011 23:00:00 +0100 4955046 http://www.medworm.com/index.php?rid=4955045&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21682680%26dopt%3DAbstract Authors: Vale LH, Mendes MM, Fernandes RS, Costa TR, Hage-Melim LI, Sousa MA, Hamaguchi A, Homsi-Brandeburgo MI, França SC, Silva CH, Pereira PS, Soares AM, Rodrigues VM Four compounds (isoquercitrin, myricetin-3-O-glucoside, catechin and gallocatechin) were isolated from lyophilized aqueous extract of Schizolobium parahyba leaves by chromatography on Sephadex LH-20, followed by semi-preparative HPLC using a C-18 column, and identified by (1)H and (13)C NMR. The compounds were then, tested against hemorrhagic and fibrinogenolytic activities of Bothrops crude venoms and isolated metalloproteinases. The inhibitors neutralized the biological and enzymatic activities of Bothrops venoms and toxins isolated from B. jararacussu and B. neuwiedi venoms. The results showed that gallocatechin an... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4955045 Thu, 16 Jun 2011 23:00:00 +0100 4955045 http://www.medworm.com/index.php?rid=4955044&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21682681%26dopt%3DAbstract Authors: Mahadeswaraswamy YH, Manjula B, Devaraja S, Girish KS, Kemparaju K The present study describes the purification and characterization of a hyaluronidase (DRHyal-II) from Daboia/Vipera russelli venom and its inhibition by β-3-(3-hydroxy-4-oxopyridyl) α-amino-propionic acid, the mimosine. Gel permeation and ion exchange chromatography were employed to isolate DRHyal-II. The molecular mass by MALDI-TOF mass spectrometry was found to be 28.3 kDa. Single band in reduced SDS-PAGE suggested the monomeric nature. It was optimally active at pH 5.5 and at 37°C and require 150 mM NaCl in the reaction mixture. It was specific to hyaluronan substrate and belongs to class-I or the neutral active enzymes. DRHyal-II was non-toxic by itself but, it potentiated the myotoxicity of VRV-PL-VIII ... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4955044 Thu, 16 Jun 2011 23:00:00 +0100 4955044 http://www.medworm.com/index.php?rid=4955043&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21682682%26dopt%3DAbstract This study confirmed the potent snake venom neutralizing properties of peptides. PMID: 21682682 [PubMed - as supplied by publisher] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4955043 Thu, 16 Jun 2011 23:00:00 +0100 4955043 http://www.medworm.com/index.php?rid=4955042&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21682683%26dopt%3DAbstract Authors: Mohamed R, Shivaprasad HV, Jameel NM, Shekar MA, Vishwanath BS L-ascorbic acid upon condensation with palmitic acid in the presence of sulphuric acid results in L-ascorbic acid-6-palmitate (AP). The effect of L-ascorbic acid derivative, AP on the pharmacological activities of purified basic multi-toxic PLA(2) enzyme, VRV-PL-VIIIa from Vipera russelli snake venom along with in vitro activities is described. AP inhibited VRV-PL-VIIIa enzyme activity in a concentration dependent manner with IC(50) value of 48.85 µM and the inhibition is found to be independent of substrate and calcium concentration. Upon investigating the in vivo pharmacological activities, it has been found that AP inhibited VRV-PL-VIIIa induced mouse paw edematogenic activity in a dose dependant manner. Intram... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4955042 Thu, 16 Jun 2011 23:00:00 +0100 4955042 http://www.medworm.com/index.php?rid=4955041&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21682684%26dopt%3DAbstract In this study 3, 4, 5-tri-hydroxy benzoic acid, the gallic acid (GA) was tested against the local toxicity of Daboia russelli (DR) venom and its purified hemorrhagic complex (HC). GA inhibited in vitro proteolytic activity of both DR venom and HC but, it did not inhibit phospholipase activity of DR venom. GA inhibited hemorrhage, edema forming, dermo- and myonecrotic activities of both HC and DR venom in in vivo experiments. GA was particularly effective against hemorrhagic activity but, GA inhibition had a greater effect on HC when compared to DR venom. The inhibition was likely due to GA induced structural changes in HC as revealed by alterations in fluorescence emission and CD spectral properties. However, the inhibition was not due to chelating property of GA as suggested by UV-visible... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4955041 Thu, 16 Jun 2011 23:00:00 +0100 4955041 http://www.medworm.com/index.php?rid=4955040&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21682685%26dopt%3DAbstract Authors: Oliveira CZ, Santos-Filho NA, Menaldo DL, Boldrini-França J, Giglio JR, Calderon LA, Stábeli RG, Rodrigues FH, Tasic L, da Silva SL, Soares AM Phospholipases A(2) (PLA(2)s) from snake venoms comprise a group of 14-18 kDa proteins, responsible for several toxic effects induced by the whole venom. Considering this, studies aiming at the search for natural inhibitors of these proteins are very important. The present work had as objectives the isolation and functional/structural characterization of a γ-type phospholipase A(2) inhibitor (PLI) from Bothrops jararacussu snake plasma, named γBjussuMIP. This acidic glycoprotein was isolated in a high purity level through affinity chromatography on CNBr-Sepharose 4B coupled with BthTX-II, showing a pI ≈ 5.5 and molecular weight of... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4955040 Thu, 16 Jun 2011 23:00:00 +0100 4955040 http://www.medworm.com/index.php?rid=4955039&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21682686%26dopt%3DAbstract Authors: Kemparaju K PMID: 21682686 [PubMed - as supplied by publisher] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4955039 Thu, 16 Jun 2011 23:00:00 +0100 4955039 http://www.medworm.com/index.php?rid=4955070&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21671863%26dopt%3DAbstract Authors: Cavallaro G, Pitarresi G, Giammona G In the last twenty years a depth study on potential pharmaceutical applications of synthetic polymers at protein-like structure as carrier for macromolecular prodrug production has been performed in academia and in industry. In particular α,β-poly(N-2-hydroxyethyl)-DL-aspartamide (PHEA), α,β-polyaspartylhydrazide (PAHy), poly(glutamic acid) (PGA), poly(aspartic acid) (PAA) and polylysine (PLL) have been extensively studied in this field. In the present review, the use of PHEA, PAHy, PGA as starting materials to prepare macromolecular prodrugs is reported and drug delivery and targeting aspects have been considered. PMID: 21671863 [PubMed - as supplied by publisher] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4955070 Mon, 13 Jun 2011 23:00:00 +0100 4955070 http://www.medworm.com/index.php?rid=4955069&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21671864%26dopt%3DAbstract Authors: Arpicco S, Dosio F, Stella B, Cattel L Research in anticancer chemotherapy has produced outstanding results, and mean survival rates have significantly improved over the last ten years. Nevertheless, all approved drugs are still characterized by narrow therapeutic windows that result mainly from their high systemic toxicity combined with their marked lack of tumor selectivity. Medicinal chemistry responds to the resulting demands with new analogues of a lead drug, or by developing prodrugs. Prodrugs are inactive compounds, which are metabolized in the body, either chemically or enzymatically, in a controlled or predictable manner, to the active parent drug. This review describes the results of strategies in prodrug development, subdivided into the principal categories of antic... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4955069 Mon, 13 Jun 2011 23:00:00 +0100 4955069 http://www.medworm.com/index.php?rid=4955067&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21671865%26dopt%3DAbstract Authors: Dhaneshwar SS, Vadnerkar G Earlier colon was considered as a black-box, acting as a site for production and temporary storage of excreta and responsible for absorption of electrolytes and water. But, with the discovery of sulfasalazine as colon-specific prodrug, the promising and challenging issue of treating local pathologies was presented with colon as an organ of significance for target-specific delivery of drugs. The need and desirable attributes of colon-specific drug delivery systems have been well recognized, extensively explored and documented in the literature. The success of a colon-specific prodrug depends on its rational design and understanding the demands of the organ to be targeted and the delivery system to be developed. The present review mainly focuses on ana... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4955067 Mon, 13 Jun 2011 23:00:00 +0100 4955067 http://www.medworm.com/index.php?rid=4955066&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21671866%26dopt%3DAbstract Authors: Dhaneshwar SS, Sharma M, Patel V, Desai U, Bhojak J There is a great emphasis on research to discover methods aimed at enhancing the efficacy of drugs and reducing their toxicity and unwanted side effects. Prodrugs are biologically inactive compounds that are converted to actual drug molecule, through biotransformation, that combine with the receptors to produce the biological action. Prodrugs can thus be considered as drugs containing specialized nontoxic protective groups utilized in a transient manner to alter or eliminate the undesirable properties of the parent drug molecule. Hypertension is one of the leading risk factors for cardiovascular disease and represents a major health and economic burden. Most of the drugs for cardiovascular diseases have low oral bioavailabili... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4955066 Mon, 13 Jun 2011 23:00:00 +0100 4955066 http://www.medworm.com/index.php?rid=4955065&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21671867%26dopt%3DAbstract Authors: Melisi D, Curcio A, Luongo E, Morelli E, Rimoli MG D-galactose is a simple and natural compound that has mainly been exploited in prodrug strategies. Galactosyl prodrugs can be considered a good approach to reach different goals in clinical drug application, especially when traditional drugs are likely to fail therapeutically owing to reasons such as the lack of site specificity, toxicity, and chemical instability. Indeed, of paramount importance is their ability to increase the selectivity of the parent compound, a phenomenon that helps to reduce the incidence of adverse effects, while preserving intact the pharmacodynamic features of the parent drug. Study results have varied according to the type of linkage between the drug and the hydroxyl group exploited. By working with ... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4955065 Mon, 13 Jun 2011 23:00:00 +0100 4955065 http://www.medworm.com/index.php?rid=4955064&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21671868%26dopt%3DAbstract Authors: Huttunen KM, Rautio J The study of prodrugs that are chemically modified bioreversible derivatives of active drug compounds to alter their undesired properties has been expanded widely during the last decades. Despite the commercial success the prodrugs have afforded, the concept is still quite unknown among many scientist especially physicians. Furthermore, many scientists regard prodrugs as a pure interest of academic research groups and not as a feasible solution to improve the delivery or targeting properties of new chemical entities, drug candidates failed in clinical trials, or drugs withdrawn from the market. Although there are still unmet needs that require addressing, prodrugs should be seen as fine-tuning tools for the successful drug research and development. This r... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4955064 Mon, 13 Jun 2011 23:00:00 +0100 4955064 http://www.medworm.com/index.php?rid=4955063&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21671869%26dopt%3DAbstract Authors: Melisi D PMID: 21671869 [PubMed - as supplied by publisher] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4955063 Mon, 13 Jun 2011 23:00:00 +0100 4955063 http://www.medworm.com/index.php?rid=4955062&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21671870%26dopt%3DAbstract Authors: Szolcsányi J, Pintér E, Helyes Z, Pethő G Release of somatostatin into the circulation from the activated TRPV1-expressing nociceptors revealed by antidromic stimulation of dorsal roots in the rat pinpointed to a novel potential drug target on these nociceptors. The review summarizes the functional, biochemical and pharmacological evidence for a novel somatostatin-mediated counter-regulatory antiinflammatory/antinociceptive "sensocrine" function in rats and guinea-pigs. To identify the somatostatin receptor subtype(s) responsible for this function, experiments were focused on actions of sstR4 receptor agonists as this subtype, similarly to sstR1, is not involved in endocrine regulation. Involvement of somatostatin and the sstR4 was revealed by using pretreatment with somato... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4955062 Mon, 13 Jun 2011 23:00:00 +0100 4955062 http://www.medworm.com/index.php?rid=4955061&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21671871%26dopt%3DAbstract Authors: Defalco J, Duncton MA, Emerling D TRPM8 belongs to the TRPM Melastatin subfamily of Transient Receptor Potential (TRP) ion channels. Activated by cool temperatures and mimetic ligands, such as menthol and icilin, TRPM8 has been shown to play a role in thermoreception and is expressed in peripheral nerves. TRPM8 is also expressed in other tissues which are not exposed to temperature fluctuations, such as the prostate. The recent advancement of a TRPM8 agonist into the clinic for the treatment of prostate cancer suggests that the channel plays a role in some human pathologies. As more drug-like and selective agonists and antagonists of TRPM8 become available, in vivo pharmacology studies will complement already published knockout data to further our understanding of the role of ... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4955061 Mon, 13 Jun 2011 23:00:00 +0100 4955061 http://www.medworm.com/index.php?rid=4955060&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21671872%26dopt%3DAbstract Authors: Strassmaier T, Bakthavatchalam R TRPA1 is a member of a superfamily of non-selective cation channels that is known to be involved in multiple physiological functions. TRPA1 is activated by a broad spectrum of chemical irritants and endogenous inflammatory compounds. An emerging role for TRPA1 in mediating pain and inflammation raises the possibility that compounds targeting TRPA1 might have significant therapeutic potential. This review discusses the broad classes of molecules that are known to act as agonists and antagonists of TRPA1 towards the aim of providing an overview of the structure and activity of TRPA1 modulators. PMID: 21671872 [PubMed - as supplied by publisher] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4955060 Mon, 13 Jun 2011 23:00:00 +0100 4955060 http://www.medworm.com/index.php?rid=4955059&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21671873%26dopt%3DAbstract Authors: Vincent F, Duncton MA TRPV4 belongs to the TRPV subfamily of Transient Receptor Potential (TRP) ion channels. This year marks the 10 year anniversary of the discovery of this polymodal ion channel which is activated by a variety of stimuli including warm temperatures, hypotonicity and endogenous lipids. Coupled with a widespread tissue distribution, this activation profile has resulted in a large number of disparate physiological functions for TRPV4. These range from temperature monitoring in skin keratinocytes to osmolarity sensing in kidneys, sheer stress detection in blood vessels and osteoclast differentiation control in bone. As knowledge of its physiological roles has expanded, interest in targeting TRPV4 modulation for therapeutic purposes has arisen and is now focused ... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4955059 Mon, 13 Jun 2011 23:00:00 +0100 4955059 http://www.medworm.com/index.php?rid=4955057&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21671874%26dopt%3DAbstract Authors: Reilly RM, Kym PR The vanilloid subfamily of transient receptor potential (TRPV) ion channels serves critical functions in sensory signaling in specialized cells and intact organisms ranging from yeast to primates. As thermosensors, chemosensors, and/or mechanosensors, these channels monitor the local environment and integrate and respond to multiple stimuli distinctively. More than a decade of research on the founding member of the subclass, TRPV1, has led to advancement of multiple antagonists into the clinic for the treatment of chronic pain. In recent years the comprehensive knowledge accessed through these studies has been applied to enhance understanding of other TRPV isoforms and, in particular, to determine whether they, too, represent promising targets for drug discov... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4955057 Mon, 13 Jun 2011 23:00:00 +0100 4955057 http://www.medworm.com/index.php?rid=4955056&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21671875%26dopt%3DAbstract Authors: Premkumar LS, Bishnoi M The transient receptor potential vanilloid 1(TRPV1) channel has been a topic of great interest, since its discovery in 1997. It is a homotetrameric non-selective cation channel predominantly expressed in a population of sensory neurons and its involvement in different modalities of pain has been extensively studied. However, TRPV1 has also been shown to be expressed in non-sensory neurons and non-neuronal cells. TRPV1 is considered as a potential target for drug development, based on its tissue distribution and its role in physiological functions. Here, we summarize the evidences for disease-related alterations in TRPV1 expression and function and review the current perspectives for the therapeutic potential of TRPV1 agonists and antagonists in the trea... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4955056 Mon, 13 Jun 2011 23:00:00 +0100 4955056 http://www.medworm.com/index.php?rid=4955055&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21671876%26dopt%3DAbstract Authors: Xia R, Samad TA, Btesh J, Jiang LH, Kays I, Stjernborg L, Dekker N Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel gated by noxious heat, vanilloids and extracellular protons. TRPV1 is acting as an important signal integrator in sensory nociceptors under physiological and pathological conditions including inflammation and neuropathy. Because of its integrative signaling properties in response to inflammatory stimuli, TRPV1 agonists and antagonists are predicted to inhibit the sensation of ongoing or burning pain that is reported by patients suffering from chronic pain, therefore offering an unprecedented advantage in selectively inhibiting painful signaling from where it is initiated. In this chapter, we firstly summarize the study in underst... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4955055 Mon, 13 Jun 2011 23:00:00 +0100 4955055 http://www.medworm.com/index.php?rid=4955053&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21671877%26dopt%3DAbstract Authors: Iadarola MJ, Mannes AJ The idea of selectively targeting nociceptive transmission at the level of the peripheral nervous system is attractive from multiple perspectives, particularly the potential lack of non-specific (non-targeted) CNS side effects. Out of the multiple TRP channels involved in nociception, TRPV1 is a strong candidate based on its biophysical conductance properties and its expression in inflammation-sensitive dorsal root ganglion neurons and their axons and central and peripheral nerve terminals. While TRPV1 antagonists have undergone extensive medicinal chemical and pharmacological investigation, for TRPV1 agonists nature has provided an optimized compound in RTX. RTX is not suitable for systemic administration, but it is highly adaptable to a variety of pain... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4955053 Mon, 13 Jun 2011 23:00:00 +0100 4955053 http://www.medworm.com/index.php?rid=4955052&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21671878%26dopt%3DAbstract Authors: Kissin I, Szallasi A In primary sensory neurons, the capsaicin receptor TRPV1 functions as a molecular integrator for a broad range of seemingly unrelated chemical and physical noxious stimuli, including heat and altered pH. Indeed, TRPV1 is thought to be a major transducer of the thermal hyperalgesia that follows inflammation and tissue injury as this response is impaired in TRPV1-deficient mice. Following the molecular cloning of TRPV1 in 1997, over a dozen companies embarked on efforts to find clinically useful TRPV1 antagonists, but side-effects and limited efficacy have thus far prevented any compounds from progressing beyond phase II. This has rekindled interest in desensitization of nociceptive neurons to TRPV1 agonists (e.g. capsaicin and its ultrapotent analog resinif... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4955052 Mon, 13 Jun 2011 23:00:00 +0100 4955052 http://www.medworm.com/index.php?rid=4955051&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21671879%26dopt%3DAbstract Authors: Blumberg PM, Pearce LV, Lee J TRPV1 has emerged as a promising therapeutic target for pain as well as a broad range of other conditions such as asthma or urge incontinence. The identification of resiniferatoxin as an ultrapotent ligand partially able to dissect the acute activation of TRPV1 from subsequent desensitization and the subsequent intense efforts in medicinal chemistry have revealed that TRPV1 affords a dramatic landscape of opportunities for pharmacological manipulation. While agonism and antagonism have represented the primary directions for drug development, the pharmacological complexity of TRPV1 affords additional opportunities. Partial agonism/partial antagonism, its modulation by signaling pathways, variable desensitization, and slow kinetics of action can all... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4955051 Mon, 13 Jun 2011 23:00:00 +0100 4955051 http://www.medworm.com/index.php?rid=4955050&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21671880%26dopt%3DAbstract Authors: Nieto-Posadas A, Jara-Oseguera A, Rosenbaum T Transient Receptor Potential (TRP) cation channels participate in several processes of vital importance in cell and organism physiology, and have been demonstrated to participate in the detection of sensory stimuli. The thermo TRP's reviewed: TRPV1 (vanilloid 1), TRPM8 (melastatin 8) and TRPA1 (ankyrin-like 1) are known to integrate different chemical and physical stimuli such as changes in temperature (noxious cold or noxious heat), changes in pH and sensing different irritant or pungent compounds. However, despite the physiological importance of these channels the mechanisms by which they detect incoming stimuli, how the sensing domains are coupled to channel gating and how these processes are connected to specific structural reg... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4955050 Mon, 13 Jun 2011 23:00:00 +0100 4955050 http://www.medworm.com/index.php?rid=4955049&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21671881%26dopt%3DAbstract Authors: Eid SR Following the cloning and characterization of the transient receptor potential vanilloid 1 (TRPV1), a growing body of research has identified the important role of TRPV1 and related channels in diverse physiological functions including temperature transduction and pain signalling. As a result, there has been a great deal of interest by the pharmaceutical industry to develop small molecule modulators of the activity of these channels for potential therapeutic use. While most of the efforts have focused on examining the role of TRPV1 in nociception, more recent work has begun to assess the therapeutic utility of targeting other TRP channels. This manuscript is aimed at introducing the reader of this special issue to the promising new developments and findings as well as e... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4955049 Mon, 13 Jun 2011 23:00:00 +0100 4955049 http://www.medworm.com/index.php?rid=4955048&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21671882%26dopt%3DAbstract Curr Top Med Chem. 2011 Jun 14; Authors: Szallasi A PMID: 21671882 [PubMed - as supplied by publisher] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4955048 Mon, 13 Jun 2011 23:00:00 +0100 4955048 http://www.medworm.com/index.php?rid=4905705&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21619508%26dopt%3DAbstract Authors: Angelucci F, Miele AE, Boumis G, Brunori M, Dimastrogiovanni D, Bellelli A Schistosomiasis is a widespread tropical parasitic disease, currently treated with Praziquantel, whose precise molecular target is actually unknown. Several other drugs are known to kill the schistosomes in vivo and in vitro, but these are seldom employed because of toxicity, high cost, complex administration or other reasons. The improvement of known drugs or the development of entirely new ones is a desirable goal, in view of the fact that strains of Schistosoma mansoni with reduced sensitivity to Praziquantel have appeared. In this review, we tried to collect the information available on known or putative macromolecular targets of schistosomicidal drugs; thus we focused on the biochemistry of the par... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4905705 Wed, 25 May 2011 23:00:00 +0100 4905705 http://www.medworm.com/index.php?rid=4905704&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21619509%26dopt%3DAbstract Authors: Hunter WN Two, simple, C5 compounds, dimethylally diphosphate and isopentenyl diphosphate, are the universal precursors of isoprenoids, a large family of natural products involved in numerous important biological processes. Two distinct biosynthetic pathways have evolved to supply these precursors. Humans use the mevalonate route whilst many species of bacteria including important pathogens, plant chloroplasts and apicomplexan parasites exploit the non-mevalonate pathway. The absence from humans, combined with genetic and chemical validation suggests that the non-mevalonate pathway holds the potential to support new drug discovery programmes targeting Gram-negative bacteria and the apicomplexan parasites responsible for causing serious human diseases, and also infections of ve... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4905704 Wed, 25 May 2011 23:00:00 +0100 4905704 http://www.medworm.com/index.php?rid=4905703&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21619510%26dopt%3DAbstract Authors: Wilkinson SR, Bot C, Kelly JM, Hall BS Chagas disease and African sleeping sickness are trypanosomal infections that represent important public health problems in Latin America and Africa, respectively. The restriction of these diseases to the poorer parts of the world has meant that they have been largely neglected and limited progress has been made in their treatment. The nitroheterocyclic prodrugs nifurtimox and benznidazole, in use against Chagas disease for >40 years, remain the only agents available for this infection. In the case of African sleeping sickness, nifurtimox has recently been added to the arsenal of medicines, with the nitroheterocycle fexinidazole currently under evaluation. For a long time, the cytotoxic mechanism of these drugs was poorly understood: n... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4905703 Wed, 25 May 2011 23:00:00 +0100 4905703 http://www.medworm.com/index.php?rid=4905702&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21619511%26dopt%3DAbstract Authors: Cassera MB, Zhang Y, Hazleton KZ, Schramm VL Malaria is a leading cause of morbidity and mortality in the tropics. Chemotherapeutic and vector control strategies have been applied for more than a century but have not been efficient in disease eradication. Increased resistance of malaria parasites to drug treatment and of mosquito vectors to insecticides requires the development of novel chemotherapeutic agents. Malaria parasites exhibit rapid nucleic acid synthesis during their intraerythrocytic growth phase. Plasmodium purine and pyrimidine metabolic pathways are distinct from those of their human hosts. Thus, targeting purine and pyrimidine metabolic pathways provides a promising route for novel drug development. Recent developments in enzymatic transition state analysis hav... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4905702 Wed, 25 May 2011 23:00:00 +0100 4905702 http://www.medworm.com/index.php?rid=4905701&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21619512%26dopt%3DAbstract Authors: Macraild CA, Anders RF, Foley M, Norton RS The invasion of host cells by malaria parasites represents an attractive target for therapeutic intervention. The role played by apical membrane antigen 1 (AMA1) in this process has been elucidated recently with the demonstration that AMA1 forms a complex with parasite rhoptry neck (RON) proteins as part of the moving junction that develops between the host cell and the invading parasite. Structural studies of AMA1 alone and in complexes with antibodies that inhibit host cell invasion have identified a conserved hydrophobic cleft that is essential to the assembly of the AMA1/RON complex. AMA1 is already established as an important candidate for inclusion in a malaria vaccine. Here we review both the structural details and functional s... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4905701 Wed, 25 May 2011 23:00:00 +0100 4905701 http://www.medworm.com/index.php?rid=4905700&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21619513%26dopt%3DAbstract Authors: Lepesheva GI, Waterman MR Pathogenic protozoa threaten lives of several hundred million people throughout the world and are responsible for large numbers of deaths globally. The parasites are transmitted to humans by insect vectors, more than a hundred of infected mammalian species forming reservoir. With human migrations, HIV-coinfections, and blood bank contamination the diseases are now spreading beyond the endemic tropical countries, being found in all parts of the world including the USA, Canada and Europe. In spite of the widely appreciated magnitude of this health problem, current treatment for sleeping sickness (Trypanosoma brucei), Chagas disease (Trypanosoma cruzi) and leishmaniasis (Leishmania spp.) remains unsatisfactory. The drugs are decades old, their efficacy a... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4905700 Wed, 25 May 2011 23:00:00 +0100 4905700 http://www.medworm.com/index.php?rid=4905699&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21619514%26dopt%3DAbstract Authors: Müller J, Hemphill A The increasing demand for novel anti-parasitic drugs due to resistance formation to well-established chemotherapeutically important compounds has increased the demands for a better understanding of the mechanism(s) of action of existing drugs and of drugs in development. While different approaches have been developed to identify the targets and thus mode of action of anti-parasitic compounds, it has become clear that many drugs act not only on one, but possibly several parasite molecules or even pathways. Ideally, these targets are not present in any cells of the host. In the case of apicomplexan parasites, the unique apicoplast, provides a suitable target for compounds binding to DNA or ribosomal RNA of prokaryotic origin. In the case of intracellular pa... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4905699 Wed, 25 May 2011 23:00:00 +0100 4905699 http://www.medworm.com/index.php?rid=4905698&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21619515%26dopt%3DAbstract Authors: de Jersey J, Holý A, Hocková D, Naesens L, Keough DT, Guddat LW Malaria remains the most serious parasitic diseases affecting humans in the world today, resulting in 1-2 million fatalities each year. Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) are the predominant causative agents. Both are responsible for widespread mortality and morbidity and are a serious socio-economic burden, especially for countries in the developing world. One of the most important defences against malaria has been the use of chemotherapeutic drugs (e.g. chloroquine, artemisinins, pyrimethamine) but these have mainly been found by serendipity. Their mechanisms was not understood at the time of their discovery and, even today, are still not unequivocal. For many of these compounds, the parasite... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4905698 Wed, 25 May 2011 23:00:00 +0100 4905698 http://www.medworm.com/index.php?rid=4905697&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21619516%26dopt%3DAbstract Authors: Guddat L PMID: 21619516 [PubMed - as supplied by publisher] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4905697 Wed, 25 May 2011 23:00:00 +0100 4905697 http://www.medworm.com/index.php?rid=4803934&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21506917%26dopt%3DAbstract Authors: McCurdy CR PMID: 21506917 [PubMed - in process] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803934 Tue, 10 May 2011 19:00:03 +0100 4803934 http://www.medworm.com/index.php?rid=4803923&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21510831%26dopt%3DAbstract Authors: Zhong H, Bowen JP Aberrant angiogenesis has been observed in many solid tumors. The formation and metastases of tumors such as non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) is very complex, often regulated by proangiogenic factors such as the vascular endothelial growth factor (VEGF) and other tyrosine kinases. The VEGFR, EGFR and mTOR pathways have played critical roles in controlling cell proliferation and angiogenesis. This paper reviews the mechanism and binding modes of recently approved tyrosine kinase inhibitors (TKIs), such as gefitinib, erlotinib, nilotinib, dasatinib, sunitinib, sorafenib, pazopanib, lapatinib, afinitor, and temsirolimus. We also cover the progresses of the recent development of tyrosine kinase inhibitors that are currently in the... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803923 Thu, 21 Apr 2011 23:00:00 +0100 4803923 http://www.medworm.com/index.php?rid=4803922&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21510832%26dopt%3DAbstract Authors: Imbimbo BP, Giardina GA According to the β-amyloid (Aβ) hypothesis, compounds that inhibit or modulate γ secretase, the pivotal enzyme that generates Aβ, are potential therapeutics for Alzheimer's disease (AD). Studies in both transgenic and non-transgenic animal models of AD have indicated that γ-secretase inhibitors, administered by the oral route, are able to lower brain Aβ concentrations. However, scanty data are available on the effects of these compounds on brain Aβ deposition after chronic administration. Behavioral studies are also scarce with only one study indicating positive cognitive effects of a peptidomimetic compound acutely administered (DAPT). γ-Secretase inhibitors may cause abnormalities in the gastrointestinal tract, thymus, spleen and skin in exper... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803922 Thu, 21 Apr 2011 23:00:00 +0100 4803922 http://www.medworm.com/index.php?rid=4803921&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21510833%26dopt%3DAbstract Authors: Corradini R, Sforza S, Tedeschi T, Totsingan F, Manicardi A, Marchelli R Peptide nucleic acids (PNAs) are polyamidic oligonucleotide analogs which have been described for the first time almost twenty years ago and were immediately found to be excellent tool in binding DNA and RNA for diagnostics and gene regulation. Their use as therapeutic agents have been proposed since early studies and recent advancements in cellular delivery systems and in the so called anti-gene strategy make them good candidates for drug development. The search for new chemical modification of PNAs is a very active field of research and new structures are continuously proposed. This review focuses on the modification of the PNA backbone, and their possible use in medicinal chemistry with an update of th... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803921 Thu, 21 Apr 2011 23:00:00 +0100 4803921 http://www.medworm.com/index.php?rid=4803920&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21510834%26dopt%3DAbstract Authors: Cavasotto CN The use of homology models in docking-based drug discovery is already established, and provides an effective and computationally affordable alternative whenever experimental structures are not available. Recent methodological studies have confirmed and benchmarked the feasibility of using structural models in docking. However, more accurate methods are expected to be developed in the near future, especially for the model refinement stage. In this review, the latest developments in homology modeling in the context of structure-based virtual screening are presented, together with the recent success stories of homology modeling in actual docking-based drug discovery endeavours. PMID: 21510834 [PubMed - as supplied by publisher] (Source: Current Topics in Medicina... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803920 Thu, 21 Apr 2011 23:00:00 +0100 4803920 http://www.medworm.com/index.php?rid=4803919&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21510835%26dopt%3DAbstract Authors: Lleó A, Saura CA γ-secretase is an aspartyl protease that cleaves a large number of substrates within the membrane environment. This multiprotein complex is responsible for the last cleavage step of the β-amyloid precursor protein (APP) that generates the amyloid-β peptide (Aβ), one of the primary components of amyloid plaques in Alzheimer's disease (AD). Over the last years, more than 70 type-I membrane proteins have been shown to be cleaved by γ-secretase. The mechanism and function of this cleavage event is yet not well understood. The γ-secretase cleavage of some substrates releases intracellular domains with critical signaling properties. In contrast, the cleavage of other substrates seems to have a mere degradative function. Knowledge about γ-secretase substrates... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803919 Thu, 21 Apr 2011 23:00:00 +0100 4803919 http://www.medworm.com/index.php?rid=4803918&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21510836%26dopt%3DAbstract Authors: Ho LT, Kulkarni SS, Lee JC The kidney plays an important role in the regulation of plasma glucose. It is estimated that greater than 99% of the renal glucose filtered by kidney glomerulus is resorbed by sodium-dependent glucose co-transporters (SGLTs), and that SGLT2 located in the proximal renal tubule achieves the most of this assignment. Studies of SGLT2 inhibitors indicate that raising renal glucose excretion by inhibiting SGLT2 helps effectively normalize the plasma glucose levels in individuals with type 2 diabetes mellitus (T2DM). This review discusses the discovery of SGLT2 inhibitors and the related structure-activity relationship (SAR) studies. The clinical trial data of dapagliflozin is also involved. PMID: 21510836 [PubMed - as supplied by publisher] (Source: C... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803918 Thu, 21 Apr 2011 23:00:00 +0100 4803918 http://www.medworm.com/index.php?rid=4803917&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21510837%26dopt%3DAbstract Authors: Wu YK, Yeh CF, Ly TW, Hung MS Since Rimonabant was withdrawn in Europe in 2008 because of its substantial CNS risk factors including depression and anxiety, the development of anti-obesity drugs targeting CB1R in the brain has been suspended and/or terminated globally. Instead, developing peripherally restricted CB1R antagonists is actively pursued in the hope that not only could they eliminate any CNS adverse effects observed with Rimonabant, but also maintain therapeutic benefits in metabolic syndrome, including obesity, type 2 diabetes, and non-alcoholic fatty liver diseases. In this review, we summarized the most recent advances that have been made on this area, with particular emphasis on various synthetic approaches, whereby the increase in polarity, water solubility and... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803917 Thu, 21 Apr 2011 23:00:00 +0100 4803917 http://www.medworm.com/index.php?rid=4803916&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21510838%26dopt%3DAbstract Authors: Sun D, Wang M, Wang Z 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the interconversion of inactive cortisone to active cortisol in a NADPH dependent manner. Excess cortisol or 11β-HSD1 leads to insulin resistance and metabolic syndrome. Inhibition of 11β-HSD1 activity has been pursued vigorously by the pharmaceutical industry as a potential therapeutic strategy for the treatment of type 2 diabetes. As a result, a large number of chemical classes have been identified as potent and selective small molecule inhibitors for 11β-HSD1. Here we review the recent progress in the discovery and development of small molecule inhibitors of 11β-HSD1 by highlighting the medicinal chemistry, SAR, in vivo pharmacodynamic effects and efficacy of a few representative classe... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803916 Thu, 21 Apr 2011 23:00:00 +0100 4803916 http://www.medworm.com/index.php?rid=4803915&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21510839%26dopt%3DAbstract Authors: Chen SJ, Jiaang WT Dipeptidyl peptidase-IV (DPP-IV), a serine protease that specifically cleaves the N-terminal dipeptide with a preference for L-proline or L-alanine at the penultimate position, is involved in the degradation of incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). GLP-1 regulates glucose homeostasis by stimulating insulin secretion, inhibiting glucagon release, and delaying gastric emptying. Intravenous GLP-1 has been shown to increase insulin secretion in response to elevated glucose levels and offers therapeutic benefit for patients with type 2 diabetes. However, the therapeutic application of GLP-1 is severely compromised by its lack of oral activity and its rapid degradation by plasma DPP-IV.... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803915 Thu, 21 Apr 2011 23:00:00 +0100 4803915 http://www.medworm.com/index.php?rid=4803914&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21510840%26dopt%3DAbstract Authors: Plancher JM Since the histamine-3 receptor (H(3)R) was cloned in 1999, huge efforts have been made by most of the key players in the pharmaceutical industry as well as in smaller biotech companies to increase the knowledge on this peculiar receptor, with the ultimate goal of bringing new drugs to the market. This review gives a survey on the most valuable chemical tools discovered so far and the significant pharmacological experiments on metabolic disease models published to date. Pharmacology of H(3)R antagonists turns out to be very complex due to various functional activities, species selectivity, presence of H(3)R isoforms and the poorly understood dichotomy in efficacy between CNS and metabolic disease models. Adding an extra layer of complexity, researchers have to cope ... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803914 Thu, 21 Apr 2011 23:00:00 +0100 4803914 http://www.medworm.com/index.php?rid=4803913&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21510841%26dopt%3DAbstract Authors: Shia KS, Chao YS PMID: 21510841 [PubMed - as supplied by publisher] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803913 Thu, 21 Apr 2011 23:00:00 +0100 4803913 http://www.medworm.com/index.php?rid=4803933&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21506926%26dopt%3DAbstract Authors: Hunter DC, Greenwood J, Zhang J, Skinner MA Kiwifruit are nutrient-dense fruit with a reputation for promoting good health. Although this could be attributed to the high vitamin C content of kiwifruit, other phytochemicals could also provide health benefits. Kiwifruit are commonly reported to be a good source of vitamin E and in addition contain phenolics and carotenoids. The antioxidant properties of kiwifruit have received attention as possible mechanisms for their health-promoting effects. In this review, the antioxidant capacity of kiwifruit is discussed in the context of biologically relevant in vitro assays for predicting antioxidant activity in a biological setting compared with chemical antioxidant assays, and the ability of kiwifruit to protect cells from dying after ... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803933 Wed, 20 Apr 2011 23:00:00 +0100 4803933 http://www.medworm.com/index.php?rid=4803932&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21506927%26dopt%3DAbstract We describe here physiological formation of a unique nitrated cyclic nucleotide, 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP) and its potent antioxidant activity. Our earlier studies revealed the NO-dependent guanine nitration in several types of cells. In fact, we identified physiological formation and functions of 8-nitro-cGMP, which is the first demonstration of a new second messenger derived from cGMP in mammals since the discovery of cGMP more than 40 years ago. Using immunocytochemical methods, we confirmed 8-nitro-cGMP formation in cultured macrophages, hepatocyte-like cells, adipocytes, and endothelial cells, depending on NO production. We further verified 8-nitro-cGMP formation via HPLC plus electrochemical detection and tandem mass spectrometry. 8-Nitro-cGMP as an e... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803932 Wed, 20 Apr 2011 23:00:00 +0100 4803932 http://www.medworm.com/index.php?rid=4803931&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21506928%26dopt%3DAbstract Authors: Serafini M, Miglio C, Peluso I, Petrosino T A large body of evidence has described the antioxidant properties of phytochemicals such as PolyPhenols (PP) in different in vitro and ex vivo models. PP have been shown to scavenge oxygen and nitrogen derived free radicals, modulating antioxidant enzymes and cellular redox transcription factors. Dietary intervention studies have shown that consumption of plant foods modulate plasma Non Enzymatic Antioxidant Capacity (NEAC), biomarker of endogenous antioxidant network, in human subjects. However the identification of the molecules responsible for this effect is far to be obtained and evidences of an antioxidant in vivo action of PP are contrasting. There is a clear discrepancy between PP concentration in body fluids and the extent of... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803931 Wed, 20 Apr 2011 23:00:00 +0100 4803931 http://www.medworm.com/index.php?rid=4803930&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21506929%26dopt%3DAbstract Authors: Bulló M, Lamuela-Raventós R, Salas-Salvadó J Oxidative stress has been involved in the aetiology of hypertension, insulin resistance, the metabolic syndrome, cardiovascular disease and other chronic conditions. Several epidemiological studies suggest that a diet rich in natural antioxidants is associated with protective effects against major diseases, especially cardiovascular disease. The Mediterranean diet is rich in fat and foods with important antioxidant properties, such as fruits and vegetables, olive oil, and nuts. In this review we focus on epidemiological evidence and clinical trials that relate the Mediterranean diet with oxidative stress markers. We focus our review on two important Mediterranean vegetable sources of potentially oxidized fat-olive oil and nuts. ... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803930 Wed, 20 Apr 2011 23:00:00 +0100 4803930 http://www.medworm.com/index.php?rid=4803929&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21506930%26dopt%3DAbstract Authors: Núñez-Córdoba JM, Martínez-González MA Cardiovascular disease represents an unparalleled proportion of the global burden of disease and will remain the main cause of mortality for the near future. Fortunately, most premature cardiovascular deaths are preventable. Therefore, prevention becomes vital and diet has shown beneficial effects to protect from CVD (CVD). Fruits and vegetables are dietary sources of natural antioxidants and it is generally accepted that antioxidants in these foods are key in explaining the inverse association between fruits and vegetables intake and the risk of developing a cardiovascular event or having elevated levels of cardiovascular risk factors. Available evidence supports the central role of oxidative stress in the atherosclerosis process an... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803929 Wed, 20 Apr 2011 23:00:00 +0100 4803929 http://www.medworm.com/index.php?rid=4803928&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21506931%26dopt%3DAbstract In conclusion, polyphenols in virtue of the plethora of protective effects manifested in various experimental models and clinical trials seem to be appropriate as dietary supplements for preventing the functional decline of organs with age. PMID: 21506931 [PubMed - as supplied by publisher] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803928 Wed, 20 Apr 2011 23:00:00 +0100 4803928 http://www.medworm.com/index.php?rid=4803927&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21506932%26dopt%3DAbstract Authors: Kawaguchi K, Matsumoto T, Kumazawa Y Oxidative stress and inflammatory responses sustained for a long period of time cause many diseases. A proinflammatory cytokine, tumor necrosis factor α (TNF-α), plays a pivotal role in the pathogenesis of chronic and auto-immune diseases. The present review, supplemented by hitherto unpublished data of the authors and their coworkers, shows that the intake of polyphenols contained in natural sources, such as hydroxytyrosol, tyrosol, oleuropein (olives), naringin and hesperidin (Citrus fruits), resveratrol, procyanidins or oligomeric procyanidin (grapes or grape seed extracts), (-)-epigallocatechin gallate (green tea) and quercetin (grapes, green tea) etc., are able to modulate chronic inflammatory diseases, such as type 2 diabetes, rheum... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803927 Wed, 20 Apr 2011 23:00:00 +0100 4803927 http://www.medworm.com/index.php?rid=4803926&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21506933%26dopt%3DAbstract Authors: Islam MS, Nagasaka R, Ohara K, Hosoya T, Ozaki H, Ushio H, Hori M Rice bran contains important bioactive phytochemicals. Among these phytochemicals, steryl ferulates including γ-oryzanol and its major components such as cycloartenyl ferulate (CAF), 24-methylenecycloartanyl ferulate (24-mCAF), β-sitosteryl ferulate (β-SF), and campesteryl ferulate have been intensively studied due to their crucial roles in pathological processes. On the basis of experimental studies published during the last decade in relation to antioxidant, anti-inflammatory, anti-ulcerogenic, hypolipidemic, anti-neoplastic, anti-diabetic, and anti-allergic phenomena, these bioactive phytochemicals are reviewed in this paper. Particularly, in vivo and in vitro studies have clarified that rice bran phytoste... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803926 Wed, 20 Apr 2011 23:00:00 +0100 4803926 http://www.medworm.com/index.php?rid=4803925&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21506934%26dopt%3DAbstract Authors: Puertollano MA, Puertollano E, de Cienfuegos GA, de Pablo MA Natural antioxidants may be defined as molecules that prevent cell damage against free radicals and are critical for maintaining optimum health in both animals and humans. In all living systems, cells require adequate levels of antioxidant defenses in order to avoid the harmful effect of an excessive production of reactive oxygen species (ROS) and to prevent damage to the immune cells. During the inflammatory processes, the activation of phagocytes and/or the action of bacterial products with specific receptors are capable of promoting the assembly of the multicomponent flavoprotein NADPH oxidase, which catalyzes the production of high amounts of the superoxide anion radical (O(2)(-)). Under these particular circumst... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803925 Wed, 20 Apr 2011 23:00:00 +0100 4803925 http://www.medworm.com/index.php?rid=4803924&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21506935%26dopt%3DAbstract Authors: Magrone T, Kumazawa Y, Jirillo E PMID: 21506935 [PubMed - as supplied by publisher] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803924 Wed, 20 Apr 2011 23:00:00 +0100 4803924 http://www.medworm.com/index.php?rid=4803948&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21470168%26dopt%3DAbstract Authors: Weill N The potential areas of applications of chemogenomic approaches are very large. Thanks to the large amount of knowledge accumulated during years of research, it is now possible to consider the binding of a ligand to a protein in a much larger context. This knowledge combined with the augmentation of computing capabilities allows global approaches to investigate biological and pharmaceutical problems. Classification of proteins, focused libraries, selectivity profiles and elaboration of new ligands for orphan receptors can all be investigated using chemogenomic. G protein-coupled receptors (GPCRs) constitute a large protein family of significant interest in pharmaceutical research. Despite this interest, and excluding the more than 360 nonolfatory proteins, the endogenou... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803948 Tue, 05 Apr 2011 23:00:00 +0100 4803948 http://www.medworm.com/index.php?rid=4803944&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21470169%26dopt%3DAbstract Authors: Andersson CR, Gustafsson MG, Strömbergsson H Chemogenomics is an emerging interdisciplinary field that lies in the interface of biology, chemistry, and informatics. Most of the currently used drugs are small molecules that interact with proteins. Understanding protein-ligand interaction is therefore central to drug discovery and design. In the subfield of chemogenomics known as proteochemometrics, protein-ligand-interaction models are induced from data matrices that consist of both protein and ligand information along with some experimentally measured variable. The two general aims of this quantitative multi-structure-property-relationship modeling (QMSPR) approach are to exploit sparse/incomplete information sources and to obtain more general models covering larger parts of ... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803944 Tue, 05 Apr 2011 23:00:00 +0100 4803944 http://www.medworm.com/index.php?rid=4803943&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21470170%26dopt%3DAbstract Authors: Crossley R, Macritchie JA, Slater MJ Thematic Analysis™ is a chemogenomic tool which has been developed and used to aid the process of GPCR drug discovery. This review covers the scientific rationale behind the development of this tool and provides examples of the successful application of the chemogenomic method in both hit finding and hit to lead stages of the drug discovery process. PMID: 21470170 [PubMed - as supplied by publisher] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803943 Tue, 05 Apr 2011 23:00:00 +0100 4803943 http://www.medworm.com/index.php?rid=4803942&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21470171%26dopt%3DAbstract Authors: Garland SL, Gloriam DE GPCR binding site-directed techniques are rapidly evolving into powerful tools for modern drug discovery. Many of these approaches bridge chemistry and biology, which are inseparable concepts in nature but are often treated as separate worlds in drug discovery and science in general. This review shows with several examples how focusing on the binding site(s) has a clear advantage when it comes to establishing sequence-correlated pharmacological profiles. By organizing and comparing sequence and structural data it is possible to "borrow" SAR from similar targets to increase the speed of lead-finding and, potentially, to produce ligands for previously intractable receptors. Sequence motifs correlated with ligands can be applied in the design of target-spec... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803942 Tue, 05 Apr 2011 23:00:00 +0100 4803942 http://www.medworm.com/index.php?rid=4803941&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21470172%26dopt%3DAbstract Authors: Kratochwil NA G protein-coupled receptors (GPCRs) share a common architecture consisting of seven transmembrane (TM) domains. Various lines of evidence suggest that this fold provides a generic binding pocket within the TM region for hosting agonists, antagonists, and allosteric modulators. Hence, an automated method was developed that allows a fast analysis and comparison of these generic ligand binding pockets across the entire GPCR family by providing the relevant information for all GPCRs in the same format. This methodology compiles amino acids lining the TM binding pocket including parts of the ECL2 loop in a so-called 1D ligand binding pocket vector and translates these 1D vectors in a second step into 3D receptor pharmacophore models. It aims to support various aspects... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803941 Tue, 05 Apr 2011 23:00:00 +0100 4803941 http://www.medworm.com/index.php?rid=4803940&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21470173%26dopt%3DAbstract Authors: Davies MN, Gloriam DE, Secker A, Freitas AA, Timmis J, Flower DR The G-protein coupled receptors - or GPCRs - comprise simultaneously one of the largest and one of the most multi-functional protein families known to modern-day molecular bioscience. From a drug discovery and pharmaceutical industry perspective, the GPCRs constitute one of the most commercially and economically important groups of proteins known. The GPCRs undertake numerous vital metabolic functions and interact with a hugely diverse range of small and large ligands. Many different methodologies have been developed to efficiently and accurately classify the GPCRs. These range from motif-based techniques to machine learning as well as a variety of alignment-free techniques based on the physiochemical properties ... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803940 Tue, 05 Apr 2011 23:00:00 +0100 4803940 http://www.medworm.com/index.php?rid=4803937&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21470174%26dopt%3DAbstract Authors: Frimurer TM, Högberg T An efficient computational method for hit and lead identification is described. The method that incorporate ligand information from physicogenetically related 7TM receptors, i.e. receptors with similar physicochemical features in the ligand binding pockets, have been developed to aid the construction of pharmacophore queries for mining of vendor and in-house databases to produce small focused libraries for a specific GPCR target. The physicogenetically related targets could be complementary to phylogenetically derived receptors and convey more relevance for the structure-based design approaches suitable for GPCR targets associated with no or limited ligand information. The approach is useful not only in identification of hits but also in the hit-to-lead... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803937 Tue, 05 Apr 2011 23:00:00 +0100 4803937 http://www.medworm.com/index.php?rid=4803936&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21470175%26dopt%3DAbstract Authors: van der Horst E, Peironcely JE, van Westen GJ, van den Hoven OO, Galloway WR, Spring DR, Wegner JK, van Vlijmen HW, Ijzerman AP, Overington JP, Bender A Chemogenomic approaches, which link ligand chemistry to bioactivity against targets (and, by extension, to phenotypes) are becoming more and more important due to the increasing number of bioactivity data available both in proprietary databases as well as in the public domain. In this article we review chemogenomics approaches applied in four different domains: Firstly, due to the relationship between protein targets from which an approximate relation between their respective bioactive ligands can be inferred, we investigate the extent to which chemogenomics approaches can be applied to receptor deorphanization. In this case i... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803936 Tue, 05 Apr 2011 23:00:00 +0100 4803936 http://www.medworm.com/index.php?rid=4803935&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21470176%26dopt%3DAbstract Authors: Garland S, Gloriam D PMID: 21470176 [PubMed - as supplied by publisher] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803935 Tue, 05 Apr 2011 23:00:00 +0100 4803935 http://www.medworm.com/index.php?rid=4803969&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21463247%26dopt%3DAbstract Authors: Velasco I Pluripotent and multipotent stem cells with differentiation potential to neural phenotypes have been described and characterized in the last decades. Embryonic stem cells, as well as neural stem cells from developing and adult nervous system, can differentiate into different types of neurons, astrocytes or oligodendrocytes. Although the initially identified actions of estradiol, progesterone and testoterone are related to sexual reproductive functions, recent evidence shows that these steroid hormones modulate development, physiology and survival of nerve cells. Furthermore, neurosteroids can be synthesized in the developing and adult nervous system. A description of the molecular modulatory actions of sex steroid hormones on the Central Nervous System is presented. ... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803969 Mon, 04 Apr 2011 23:00:00 +0100 4803969 http://www.medworm.com/index.php?rid=4803968&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21463248%26dopt%3DAbstract Authors: Picazo O, Espinosa-Raya J, Jiménez-Trejo F, Suarez J Two of the most studied brain areas related with learning and memory are prefrontal cortex and hippocampus. However, serious inconsistencies arise when these regions are analyzed in relation to the role of estrogens on cognitive deterioration. Some of these contradictions are reviewed in the context of the recently proposed critical period hypothesis, which takes into account the frame-time after cessation of ovarian function. Other factors related with cognition and influenced by estrogens include their role on; a) cholinergic central transmission, b) spinogenesis and synaptogenesis at hippocampus, and c) classical genomic and rapid non genomic effects. Understanding the cellular and molecular basis of these phenomena is v... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803968 Mon, 04 Apr 2011 23:00:00 +0100 4803968 http://www.medworm.com/index.php?rid=4803967&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21463249%26dopt%3DAbstract Authors: Yanes LL, Romero DG, Iliescu R, Reckelhoff JF Postmenopausal women make up one of the fastest growing populations in the United States. Women typically have a higher incidence of cardiovascular disease following menopause. One of the major risk factors for cardiovascular disease is hypertension, and after menopause, blood pressure (BP) increases progressively in women. Also after menopause, the progression of renal disease increases in women compared with aged matched men. However, the mechanism(s) responsible for the post-menopausal increase in BP and renal injury are yet to be elucidated. Moreover the best therapeutic options to treat postmenopausal hypertension in women are not clear. Hypertension in postmenopausal women are usually associated with other cardiovascular risk... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803967 Mon, 04 Apr 2011 23:00:00 +0100 4803967 http://www.medworm.com/index.php?rid=4803966&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21463250%26dopt%3DAbstract Authors: Morimoto S, Jiménez-Trejo F, Cerbón M Traditionally the role of sexual steroid hormones was focused primarily on reproductive organs: the breast, female reproductive tract (uterus, mammary gland, and ovary), and male reproductive tract (testes, epididymis and prostate), however our current understanding of tissue-specific effects of sex steroids has elucidated new aspects in its functionality. Recent data have shown that many other tissues are targets of those hormones in addition to classical reproductive organs. The pancreas (which performs both endocrine and exocrine functions), has proven to be an extragonadal target of sexual steroid hormone action. The endocrine pancreas has a pivotal role on carbohydrate homeostasis and deterioration in function produces diabetes. Dia... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803966 Mon, 04 Apr 2011 23:00:00 +0100 4803966 http://www.medworm.com/index.php?rid=4803965&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21463251%26dopt%3DAbstract Authors: Muñoz-Cruz S, Togno-Pierce C, Morales-Montor J Sex hormones play an important role as modulators of the immune system. A growing body of evidence shows reciprocal relationship between sex steroids and the immune system. Since the innate immune response determines the type of adaptive immune response, hormonal effects on the innate immune response may affect subsequent adaptive immunity. The sex steroids estrogens, progesterone and testosterone regulate growth, differentiation, survival and function of many cell types involved in homeostasis and immunity. The presence of sex steroid receptors on immune cells indicates that sex steroids may exert their biological effects by binding to these receptors. Sex steroids and immunity are closely connected, and their mutual regulation ... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803965 Mon, 04 Apr 2011 23:00:00 +0100 4803965 http://www.medworm.com/index.php?rid=4803964&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21463252%26dopt%3DAbstract Authors: Paris JJ, Frye CA Gestational stress may have lasting deleterious effects on neuro-cognitive development of offspring. Progesterone (P), and its 5α-reduced metabolites, dihydroprogesterone (DHP) and 5α-pregnan-3α-ol-20-one (3α,5α-THP), maintain pregnancy, and can have effects on cognitive performance and/or neuronal integrity. However, whether some of the deleterious effects of gestational stress on cognitive and neural processes may be related to progestogen formation is not known. Pregnant rat dams were exposed to a regimen of variable stressors (including forced swim, restraint, fasting, social stress, and exposure to cold and light) on gestational days 17-21 or were minimally-handled controls. Male and female offspring were cross-fostered to non-manipulated dams and a... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803964 Mon, 04 Apr 2011 23:00:00 +0100 4803964 http://www.medworm.com/index.php?rid=4803963&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21463253%26dopt%3DAbstract Authors: Guarner PT, El Hafidi M, Baños G In the metabolic syndrome (MS), a condition that associates three or more pathologies such as hypertension, central obesity, type II diabetes, insulin resistance and dyslipidemias, the kidneys are severely affected. The pathological alterations in the kidneys, associated with MS, may be modified by sex hormone levels. In general, estrogens are a protection against the development of cardiovascular and renal diseases in humans and experimental models, but androgens may have an opposite effect. Among the metabolic systems that can be modulated by sex hormones in the kidney, the more important are: renin-angiotensin-aldosterone system, arachidonic acid metabolism, nitric oxide system and renal extra-cellular matrix proteins. These are metabolic p... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803963 Mon, 04 Apr 2011 23:00:00 +0100 4803963 http://www.medworm.com/index.php?rid=4803962&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21463254%26dopt%3DAbstract Authors: Martocchia A, Stefanelli M, Cola S, Falaschi P A sexual dymorphism in the immune response has been described and females display an increased incidence of autoimmune diseases. Experimental data show that sex steroids influence immune cell development and have immunomodulatory effects. The distribution, the action (genomic and nongenomic), the sex and tissue-depending expression pattern of estrogen, progesterone and androgen receptors and their functional disruptions in corresponding receptor knockout animals will be discussed, pointing out the difference among sex steroid hormones. Recent advances indicate an immunomodulatory role of sex steroids in the pathogenesis of systemic lupus erythematosus, multiple sclerosis and rheumatoid arthritis. The outcomes of the clinical trial... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803962 Mon, 04 Apr 2011 23:00:00 +0100 4803962 http://www.medworm.com/index.php?rid=4803956&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21463255%26dopt%3DAbstract Authors: Cabrera-Muñoz E, Hernández-Hernández OT, Camacho-Arroyo I Progesterone (P) participates in the regulation of several reproductive processes such as ovulation and sexual behavior, however, this hormone also participates in non-reproductive processes, such as neural excitability, learning and memory, and pathological processes such as cancer. P mainly elicits its effects by interaction with its intracellular receptor (PR), which is a ligand-activated transcription factor that modifies the expression of genes involved in the control of cell growth and proliferation, such as vascular endothelial growth factor and epidermal growth factor receptor. Two PR isoforms have been reported: PR-B and PR-A, which present different function and regulation. PR isoforms are expressed in U373... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803956 Mon, 04 Apr 2011 23:00:00 +0100 4803956 http://www.medworm.com/index.php?rid=4803951&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21463256%26dopt%3DAbstract Authors: Montor JM, Satoskar A, Terrazas LI PMID: 21463256 [PubMed - as supplied by publisher] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803951 Mon, 04 Apr 2011 23:00:00 +0100 4803951 http://www.medworm.com/index.php?rid=4803976&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21446908%26dopt%3DAbstract Authors: Thompson HL, Manilay JO Embryonic stem cells (ESC) can potentially be manipulated in vitro to differentiate into cells and tissues of all three germ layers. This pluripotent feature is being exploited to use ESC-derived tissues as therapies for degenerative diseases and replacement of damaged organs. Although their potential is great, the promise of ESC-derived therapies will be unfulfilled unless several challenges are overcome. For example, inefficient production of ESC-derived tissues before transplantation, inability of ESC-derived tissues to integrate well into the adult microenvironments due to developmental stage incompatibility, or active immune rejection of the ESC-derived graft are all potential challenges to successful ESC-derived therapies. One way to induce immuno... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803976 Tue, 29 Mar 2011 23:00:00 +0100 4803976 http://www.medworm.com/index.php?rid=4803975&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21446909%26dopt%3DAbstract Authors: Talbot P, Lin S Given the vast number of chemicals that are released into the environment each year, it is imperative that we develop new predictive models to identify toxicants before unavoidable exposure harms the health of humans and other organisms. In vitro models are especially attractive in predictive toxicology as they can greatly reduce assay costs and animal usage while identifying those chemicals that may require further in vivo evaluation. With the derivation of both mouse and human embryonic stem cells, new opportunities have developed that could revolutionize the field of predictive toxicology. Stem cells themselves can be used to model pre-implantation development, or they can be used during or after differentiation and thereby model post-implantation developmen... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803975 Tue, 29 Mar 2011 23:00:00 +0100 4803975 http://www.medworm.com/index.php?rid=4803974&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21446910%26dopt%3DAbstract Authors: Didwania M, Didwania A, Mehta G, Basak GW, Yasukawa S, Takayama S, de Necochea-Campion R, Srivastava A, Carrier E Due to the recent advancements in stem cell biology and engineering, scientists have been increasingly interested in creating in vitro niches for embryonic and adult stem cells, and, following induction and differentiation with the appropriate media, the production of large scale blood production. This artificially created niche for hematopoietic cells will be composed of three materials: the stem cells themselves, the scaffold surrounding the stem cell, and the media used to expand and differentiate the stem cells. This paper will examine the recent advancements in technology for each of these relating to the development of an artificial stem cell niche. Many key ... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803974 Tue, 29 Mar 2011 23:00:00 +0100 4803974 http://www.medworm.com/index.php?rid=4803973&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21446911%26dopt%3DAbstract Authors: Dhawan P, Ahmad R, Srivastava AS, Singh AB Normal tissue homeostasis involves a careful balance between the normal cell loss and renewal. Stem and progenitor cells help maintain this precise and fine balance through their ability of self-renewal in a tightly regulated manner. In this regard, the gastrointestinal epithelium is unique in that cell proliferation, differentiation, and apoptosis occur in an orderly fashion along the crypt-villus axis. The colonic crypt is primarily a proliferative compartment, is monoclonal and is maintained by stem cells. The concept of tissue stem cells capable of giving rise to all differentiated cells within a given tissue has led to the concept of a cellular hierarchy in tissues and in tumors including colorectal cancer (CRC). Thus, only a few... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803973 Tue, 29 Mar 2011 23:00:00 +0100 4803973 http://www.medworm.com/index.php?rid=4803972&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21446912%26dopt%3DAbstract Authors: Inoges S, Lopez-Diaz de Cerio A, Sampol A, Nieto J, Soria E, Villanueva H, Pastor F, Bendandi M Several types of B-cell malignancy, including but not limited to multiple myeloma and follicular lymphoma, are still considered incurable. In a substantial number of cases, patients must undergo either autologous or allogeneic stem cell transplantation as a standard of care procedure for their disease. Among experimental treatments for multiple myeloma and follicular lymphoma, idiotypic vaccination has been attempted over the last two decades with variable degrees of success. Few clinical trials have combined stem cell transplant procedures with idiotypic vaccination, and they are the subject of this review, which will also include some of our original data, as well as our overall e... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803972 Tue, 29 Mar 2011 23:00:00 +0100 4803972 http://www.medworm.com/index.php?rid=4803971&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21446913%26dopt%3DAbstract Authors: Pillai RG With advances in stem cell biology, tissue engineering is becoming increasingly powerful for tissue regeneration. Stem cells with capacity of multilineage and self-renewal are an ideal cell source for tissue engineering. This review focus on discussing the potential strategies including stem cell sources, bio-scaffolds, mechanical stimulation, genetic modification and co-culture techniques to direct ocular-lineage differentiation of stem cells for complete or partial eye regeneration and research. Attempts to use embryonic and somatic stem cells as seed cells for ocular tissue engineering have achieved encouraging results. The combination of chemical and physical signals in stem cell microenvironment could be regulated to induce differentiation of the embryonic stem ... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803971 Tue, 29 Mar 2011 23:00:00 +0100 4803971 http://www.medworm.com/index.php?rid=4803970&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21446914%26dopt%3DAbstract Authors: Srivastava AS PMID: 21446914 [PubMed - as supplied by publisher] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803970 Tue, 29 Mar 2011 23:00:00 +0100 4803970 http://www.medworm.com/index.php?rid=4803912&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21513493%26dopt%3DAbstract Authors: Tartari CJ, Scapozza L, Gambacorti-Passerini C Anaplastic Lymphoma Kinase (ALK) is a receptor tyrosine kinase that belongs to the Insulin receptor subfamily involved as full length receptor in neural development. Even if the expression of ALK protein is down-regulated in the adults, the ALK full length is expressed in different types of tumors. Moreover, chromosomal rearrangements, involving the alk gene, can occur leading the formation of different ALK fusion proteins characterized by the kinase domain of ALK fused to several partners that determine cellular localization. Structural investigation and characterization of the ALK kinase domain in absence of its crystal structure constitutes basis of development of ALK small molecule inhibitors. Here, we described normal functio... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803912 Mon, 28 Mar 2011 23:00:00 +0100 4803912 http://www.medworm.com/index.php?rid=4803911&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21513494%26dopt%3DAbstract Authors: Kleppe R, Krakstad C, Selheim F, Kopperud R, Døskeland SO The prototype second messenger cAMP and its major mediator, the cAMP-dependent protein kinase (PKA), is able to control simultaneously multiple processes within the same cell. This appears to be achieved through its unique dissociative regulation and the spatiotemporal regulation of both cAMP and PKA. The widespread tissue distribution and physiological function of this pathway makes it an attractive, but challenging pharmacological target. We will discuss current progress in manipulating the fine-tuning of PKA, and outline so far underexploited possibilities for therapy, such as novel ways to target specific substrates and catalytic cycle intermediates of PKA. An attractive strategy to achieve a more focused pharmacol... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803911 Mon, 28 Mar 2011 23:00:00 +0100 4803911 http://www.medworm.com/index.php?rid=4803910&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21513495%26dopt%3DAbstract Authors: Gennäs GB, Talman V, Yli-Kauhaluoma J, Tuominen RK, Ekokoski E The second messenger diacylglycerol (DAG) plays a central role in the signal transduction of G-protein coupled receptors and receptor tyrosine kinases by binding to C1 domain of effector proteins. C1 domain was first identified in protein kinase C (PKC) which comprises a family of ten isoforms that play roles in diverse cellular processes such as proliferation, apoptosis and differentiation. Aberrant signaling through PKC isoforms and other C1 domain-containing proteins has been implicated in several pathological disorders. Drug discovery concerning C1 domains has exploited both natural products and rationally designed compounds. Currently, molecules from several classes of C1 domain-binding compounds are in clini... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803910 Mon, 28 Mar 2011 23:00:00 +0100 4803910 http://www.medworm.com/index.php?rid=4803909&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21513496%26dopt%3DAbstract Authors: Danilenko VN, Osolodkin DI, Lakatosh SA, Preobrazhenskaya MN, Shtil AA Signaling through protein kinases is an evolutionary conserved, widespread language of biological regulation. The eukaryotic type serine-threonine protein kinases (STPKs) found in normal human microbiote and in pathogenic bacteria play a key role in regulation of microbial survival, virulence and pathogenicity. Therefore, down-regulation of bacterial STPKs emerges as an attractive therapeutic approach to cure infections. In this review we focused on actinobacterial STPKs to demonstrate that these enzymes can be used for crystal structure studies, modeling of 3D structure, construction of test systems and design of novel chemical libraries of low molecule weight inhibitors. In particular, the prototypic phar... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803909 Mon, 28 Mar 2011 23:00:00 +0100 4803909 http://www.medworm.com/index.php?rid=4803908&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21513497%26dopt%3DAbstract Authors: Sarno S, Papinutto E, Franchin C, Bain J, Elliott M, Meggio F, Kazimierczuk Z, Orzeszko A, Zanotti G, Battistutta R, Pinna LA CK2 denotes a pleiotropic, constitutively active protein kinase whose abnormally high level in many cancer cells is held as an example of "non oncogene addiction". A wide spectrum of cell permeable, fairly specific ATP site-directed CK2 inhibitors are currently available which are proving useful to dissect its biological functions and which share the property of inducing apoptosis of cancer cells with no comparable effect on their "normal" counterparts. One of these, CX-4945, has recently entered clinical trials for the treatment of advanced solid tumors, Castelman's disease and multiple myeloma. The solution of a wide range of 3D structures of inhibito... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803908 Mon, 28 Mar 2011 23:00:00 +0100 4803908 http://www.medworm.com/index.php?rid=4803907&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21513498%26dopt%3DAbstract Authors: Marston A Many of the protein kinase activators and inhibitors presently under investigation are natural products or are derivatives of natural products. Since over 500 kinases are encoded by the human genome, the task is to discover modulatory compounds which have high specificity for a single enzyme. Many different low molecular weight compounds have been studied for activity. These come from various sources, such as plants, marine organisms, microorganisms and cyanobacteria. The search for specific inhibitors is mainly performed in cell-based assays. PMID: 21513498 [PubMed - as supplied by publisher] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803907 Mon, 28 Mar 2011 23:00:00 +0100 4803907 http://www.medworm.com/index.php?rid=4803906&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21513499%26dopt%3DAbstract Authors: Tolle N, Kunick C Paullones are a class of molecules structurally based on the 7,12-dihydroindolo[3,2-d][1]benzazepin-6(5H)-one parent scaffold. Many of these structures are inhibitors of certain protein kinases, namely cyclin-dependent kinases and glycogen synthase kinase-3. Being well referenced in the literature on the one hand and commercially available on the other hand, paullones have been used as biochemical tools in basic research and drug development for more than a decade. This review gives an overview over the published reports regarding chemistry, biological activity and pharmacological applications of paullone derivatives. PMID: 21513499 [PubMed - as supplied by publisher] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803906 Mon, 28 Mar 2011 23:00:00 +0100 4803906 http://www.medworm.com/index.php?rid=4803905&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21513500%26dopt%3DAbstract Authors: Rechfeld F, Gruber P, Hofmann J, Kirchmair J In recent years the development of small organic molecules modulating protein-protein interactions (P-PIs) has drawn major attention in both academic and industrial research. Despite the appreciable progress being made, targeting such extensive interaction areas with comparatively small, drug-like agents has proven to be an ambitious objective. This review highlights the reasons rendering this task highly challenging and provides an overview on the latest developments in rational design approaches for P-PI modulators. The significance, scope and limitations of computational methods in this particular field of research are analyzed. Recent successfully identified and designed P-PI modulators are discussed. Thereby, particular focus i... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803905 Mon, 28 Mar 2011 23:00:00 +0100 4803905 http://www.medworm.com/index.php?rid=4803904&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21513501%26dopt%3DAbstract Authors: Yli-Kauhaluoma J, Tuominen RK PMID: 21513501 [PubMed - as supplied by publisher] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4803904 Mon, 28 Mar 2011 23:00:00 +0100 4803904 http://www.medworm.com/index.php?rid=4638013&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21418014%26dopt%3DAbstract Authors: Bernhardt PV, Richardson DR PMID: 21418014 [PubMed - in process] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4638013 Mon, 28 Mar 2011 06:00:08 +0100 4638013 http://www.medworm.com/index.php?rid=4638012&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21418015%26dopt%3DAbstract Authors: Piali L, Richardson DR PMID: 21418015 [PubMed - in process] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4638012 Mon, 28 Mar 2011 06:00:08 +0100 4638012 http://www.medworm.com/index.php?rid=4638031&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21401493%26dopt%3DAbstract Authors: Lopes LV, Sebastião AM, Ribeiro JA Adenosine is a naturally occurring nucleoside present ubiquitously throughout the body as a metabolic intermediate. Besides its metabolic role within the cells, adenosine is released into the extracellular space either by neurons or astrocytes acting as a neuromodulator. Extracellular adenosine exerts its action by activating multiple G-protein coupled receptors (subtypes A(1), A(2A), A(2B) and A(3)) having a wide range of physiological effects in the brain. Adenosine levels rise markedly in response to ischemia, hypoxia, excitotoxicity or inflammation being a neuroprotectant under these conditions. However, adenosine may also contribute to neuronal damage and cell death in other circumstances. These actions are firmly established using mult... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4638031 Mon, 14 Mar 2011 00:00:00 +0100 4638031 http://www.medworm.com/index.php?rid=4638030&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21401494%26dopt%3DAbstract Authors: Boison D Nucleoside receptors are known to be important targets for a variety of brain diseases. However, the therapeutic modulation of their endogenous agonists by inhibitors of nucleoside metabolism represents an alternative therapeutic strategy that has gained increasing attention in recent years. Deficiency in endogenous nucleosides, in particular of adenosine, may causally be linked to a variety of neurological diseases and neuropsychiatric conditions ranging from epilepsy and chronic pain to schizophrenia. Consequently, augmentation of nucleoside function by inhibiting their metabolism appears to be a rational therapeutic strategy with distinct advantages: (i) in contrast to specific receptor modulation, the increase (or decrease) of the amount of a nucleoside will affec... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=4638030 Mon, 14 Mar 2011 00:00:00 +0100 4638030