Current Topics in Medicinal ChemistryThis is an RSS file. You can use it to subscribe to this data in your favourite RSS reader, such as GoogleReader, or to display this data on your own website or blog. Subscribe to this data using MyMedWorm.Subscribe to this data using GoogleReader.Subscribe to this data using Bloglines.Subscribe to this data using MyYahoo.

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Synthesis and Biological Activity of Wuweizisu C and Analogs.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Lignans are widely distributed in nature. The earliest recorded medicinal use of lignans dated back to over 1000 years ago. Lignan-rich plant products were also active ingredients in Chinese and Japanese folk medicines for the treatment of various diseases. The dried root and stem of this plant are listed in the Chinese pharmacopoeia for the treatment of rheumatoid arthritis, gastric, duodenal ulcers and many other diseases. This review highlights synthetic strategies for the Wuweizisu C analogs and the important pharmacological activities as well as therapeutic findings related to the treatment of HBV and other diseas...
Source: Current Topics in Medicinal Chemistry - November 11, 2009 Category: Chemistry Authors: Wang Q, Li YF, Chang JB Tags: Curr Top Med Chem Source Type: journals

Nordihydroguaiaretic Acid Analogues: Their Chemical Synthesis and Biological Activities.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Nordihydroguaiaretic acid is a natural occurring lignan mainly isolated and commercially produced from desert plant, creosote bush (Larrea divaricata Cav. Or Corillea tridentate), which can be widely found in the border zone of southern of USA and northern of Mexico. During past 100 years, extensive research has demonstrated that nordihydroguaiaretic acid and its synthetic analogues are potentially useful in treating diseases related to cancers, diabetes, viral, bacterial infections, and inflammation. Remarkably, terameprocol, a tetra-O-methyl derivative of nordihydroguaiaretic acid, is currently in Phase I/II clinical...
Source: Current Topics in Medicinal Chemistry - November 11, 2009 Category: Chemistry Authors: Chen Q Tags: Curr Top Med Chem Source Type: journals

Chemo-enzymatic Transformation of Taxanes and Their Reversal Activity towards MDR Tumor Cells.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Over 200 derivatives have been obtained through chemo-enzymatic transformation of the taxanes derived from cell cultures of Taxus chinensis. The reversal activity towards MDR tumor cells and cyto-toxicity of most these compounds were evaluated, and several derivatives exhibited powerful MDR reversal activity. The substrate-specificities of the two most important biotransformation reactions-C-7beta and 9alpha hydroxylations, were investigated and preliminarily concluded. In addition, some key intermediates in hypothetically biosynthetic pathway of taxoid were obtained. These results indicate that biotransformation combi...
Source: Current Topics in Medicinal Chemistry - November 11, 2009 Category: Chemistry Authors: Dai J Tags: Curr Top Med Chem Source Type: journals

The Potential of Natural Products as Effective Treatments for Allergic Inflammation: Implications for Allergic Rhinitis.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The impact of natural products on human health has been enormous, and the study of natural products continues to influence research in the fields of chemistry, biology, and ecology. Historically, the majority of our medicines originate from natural products and their synthetic derivatives, many of which have taught us valuable lessons about biology. While advances in synthetic and combinatorial chemistry have given rise to notable successes in the development of new drugs, the perceived value of natural products in the treatment of allergic disease has yet to be fully explored. The immune system is a highly complex, in...
Source: Current Topics in Medicinal Chemistry - November 11, 2009 Category: Chemistry Authors: Kulka M Tags: Curr Top Med Chem Source Type: journals

Biosynthesis of Bacterial Aromatic Polyketides.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Aromatic polyketides represent important members of the family of polyketides, which have displayed a wide assortment of bioactive properties, such as antibacterial, antitumor, and antiviral activities. Bacterial aromatic polyketides are mainly synthesized by type II polyketide synthases (PKSs). Whereas malonyl-CoA is exclusively used as the extender unit, starter units can vary in different aromatic polyketide biosynthetic pathways, leading to a variety of polyketide backbones. Once the polyketide chains are elongated by the minimal PKSs to the full length, the immediate tailoring enzymes including ketoreductases, oxy...
Source: Current Topics in Medicinal Chemistry - November 11, 2009 Category: Chemistry Authors: Zhan J Tags: Curr Top Med Chem Source Type: journals

Pentacyclic Triterpenoids and Their Saponins with Apoptosis-inducing Activity.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Pentacyclic triterpenoids exert their antitumor activity through different mechanisms, one of which is apoptosis induction. Although there are many reports on the apoptosis inducing activity of pentacyclic triterpenoids, a systematic survey and discussion on their structure-activity relationships (SARs) is still lacking. In this review, we summarized such activity of oleanane, ursane and lupane type triterpenoids, the most abundant pentacyclic triterpene prototypes in plants. Their structural characteristics responsible for the activity are also discussed, in order to unravel their SARs for the apoptotic induction and ...
Source: Current Topics in Medicinal Chemistry - November 11, 2009 Category: Chemistry Authors: Wang SR, Fang WS Tags: Curr Top Med Chem Source Type: journals

Polyisoprenylated Benzophenones from Clusiaceae: Potential Drugs and Lead Compounds.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Many new polyisoprenylated benzophenones with a bicyclo[3.3.1]-nonane-2,4,9-trione core structure have been isolated from plants in the Clusiaceae family, and their potent biological properties have been the subject of several studies. This review summarizes the biological activities reported for these secondary metabolites including cytotoxic, antimicrobial, antioxidant, and anti-inflammatory activities. Our efforts during the past years have foremost been directed towards isolating new polyisoprenylated benzophenones, as well as understanding the possible target and mechanism of action through which these compounds a...
Source: Current Topics in Medicinal Chemistry - November 11, 2009 Category: Chemistry Authors: Acuña UM, Jancovski N, Kennelly EJ Tags: Curr Top Med Chem Source Type: journals

Low Molecular Weight and Oligomeric Chitosans and Their Bioactivities.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Chitosan is one of the most abundant marine-based biopolymers. Low molecular weight and oligomeric chitosans are water-soluble hydrolysates of chitosan. They have been shown to have a wide range of biological activities and industrial applications. In particular, low molecular weight and oligomeric chitosans have been reported to have the health benefits such as immunity regulation, anti-tumor, liver protection, blood lipids lowering, anti-diabetic, antioxidant and anti-obesity. In this paper, the preparation and analytical methods, and bioactivities of these low molecular weight and oligomeric chitosans were reviewed,...
Source: Current Topics in Medicinal Chemistry - November 11, 2009 Category: Chemistry Authors: Yin H, Du Y, Zhang J Tags: Curr Top Med Chem Source Type: journals

Anticancer Drugs Discovery and Development from Marine Organism.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The chemical and biological diversity of the different marine evolutionary group is endless and therefore, this is an amazing resource for the discovery of new anticancer drugs. Comprising 34 of the 36 Phyla of life, marine ecosystems are indeed our last genetic diversity and biotechnological boundary; terrestrial systems possess only 17 Phyla. Sponges, coelenterates and microorganisms are the foremost resources of therapeutic compounds. Algae, echinoderms, tunicates, mollusks, bryozoans are also the sources of anticancer drugs from marine resources. We highlight the past and current status of marine anticancer pharmac...
Source: Current Topics in Medicinal Chemistry - November 11, 2009 Category: Chemistry Authors: Chakraborty C, Hsu CH, Wen ZH, Lin CS Tags: Curr Top Med Chem Source Type: journals

Exploring and Exploiting Microbial Diversity through Metagenomics for Natural Product Drug Discovery.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Microorganisms of millions species exist in every corner of the Earth, and form a dynamic genetic reservoir that are not clearly revealed and categorized due to barrier in current cultivation technology. Their applications in biomedical and environmental aspects are more than satisfactory. However, the situation has drastically changed during the turn of the century because of the rapid development of phylogenetic studies based on rRNA sequencing independent of standard laboratory cultivation. More recently, high throughput sequencing technology which enables direct sequencing of community DNA for metagenomic analyses ...
Source: Current Topics in Medicinal Chemistry - November 11, 2009 Category: Chemistry Authors: Li X, Guo J, Dai S, Ouyang Y, Wu H, Sun W, Wang G Tags: Curr Top Med Chem Source Type: journals

Chemical and Biological Explorations of the Family of CC-1065 and the Duocarmycin Natural Products.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
CC-1065, the duocarmycins and yatakemycin are members of a family of ultrapotent antitumour antibiotics that have been the subject of extensive investigations due to their mode of action and potential in the design of new anticancer therapeutics. The natural products and their analogues exert their effects through a sequence selective alkylation of duplex DNA in the minor groove at the N3 of adenine. An understanding of their structure and its effect on biological activity has been derived through chemical synthesis and has also generated new potential lead compounds. These studies form the first section of the review....
Source: Current Topics in Medicinal Chemistry - November 11, 2009 Category: Chemistry Authors: Ghosh N, Sheldrake HM, Searcey M, Pors K Tags: Curr Top Med Chem Source Type: journals

Editorial.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
PMID: 19860704 [PubMed - in process] (Source: Current Topics in Medicinal Chemistry)
Source: Current Topics in Medicinal Chemistry - October 30, 2009 Category: Chemistry Authors: Reitz AB Tags: Curr Top Med Chem Source Type: journals

Sugar sulfamates for seizure control: discovery and development of topiramate, a structurally unique antiepileptic drug.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
This article discusses research results and events surrounding the discovery and development of topiramate. PMID: 19860705 [PubMed - in process] (Source: Current Topics in Medicinal Chemistry)
Source: Current Topics in Medicinal Chemistry - October 30, 2009 Category: Chemistry Authors: Maryanoff BE Tags: Curr Top Med Chem Source Type: journals

RNAi and related technologies: applications in medicinal chemistry and drug discovery.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
PMID: 19860706 [PubMed - in process] (Source: Current Topics in Medicinal Chemistry)
Source: Current Topics in Medicinal Chemistry - October 30, 2009 Category: Chemistry Authors: Morris K, McAlpine S Tags: Curr Top Med Chem Source Type: journals

RNA interference-based gene expression strategies aimed at sustained therapeutic inhibition of HIV.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The naturally-occurring RNA interference (RNAi) pathway represents a powerful tool for the sequence-specific post-transcriptional silencing of gene expression. By exploiting the endogenous mammalian RNAi pathway, several expression-based strategies have been developed to inhibit human immunodeficiency virus (HIV) gene expression and replication. This approach potentially has utility as a protective 'therapeutic vaccine' of virus-susceptible lymphocytes. In this review we discuss new developments aimed at improving efficacy and delivery of novel RNAi-based gene expression antiviral strategies. Particular attention is gi...
Source: Current Topics in Medicinal Chemistry - October 30, 2009 Category: Chemistry Authors: Barichievy S, Saayman S, Arbuthnot P, Weinberg MS Tags: Curr Top Med Chem Source Type: journals

Transcriptional regulation by promoter targeted RNAs.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Small RNA molecules, including small interfering RNA (siRNA) and micro RNA (miRNA), have rapidly emerged as important regulators of gene expression. Recent articles have demonstrated RNA mediated complex induced transcriptional gene silencing (TGS) occurring in the nucleus. Originally the small RNA mediated TGS pathway has been reported in yeast and plants, currently a number of articles strongly suggest that this newly established gene silencing mechanism is present in mammals. RNA mediated TGS has been reported for various human promoters including inhibition of tumor susceptibility genes, X-chromosome inactivation a...
Source: Current Topics in Medicinal Chemistry - October 30, 2009 Category: Chemistry Authors: Suzuki K, Kelleher AD Tags: Curr Top Med Chem Source Type: journals

Peptide mediated siRNA delivery.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Applying RNA interference to silence a specific gene has opened a new and promising avenue of gene therapy. But a key bottleneck is the poor stability and inability of naked siRNA to translocate through cell membranes. Among several delivery systems, cationic peptides capable of penetrating cell membranes have drawn attention due to their structural and functional versatility, potential biocompatibility and ability to target cells. In this review, different classes of peptides employed in siRNA delivery are reviewed. In particular, a new class of siRNA delivery peptides with high transfection efficiency and low cytotox...
Source: Current Topics in Medicinal Chemistry - October 30, 2009 Category: Chemistry Authors: Jafari M, Chen P Tags: Curr Top Med Chem Source Type: journals

Enhanced gene delivery and/or efficacy by functional peptide and protein.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
RNA interference (RNAi) is an attractive phenomenon for practical use that specifically inhibits gene expression and is carried out by small double-stranded RNAs (dsRNAs) including small interfering RNA (siRNA) or short hairpin RNA (shRNA). In addition, RNAi is of great interest for clinical use to cure refractory diseases related to the expression of a specific gene. To achieve gene silencing in the body, a sufficient amount of dsRNA must be delivered and internalized into target cells. However, dsRNAs have a large molecular weight and net negative charge, which limits their membrane-permeating ability. Moreover, dsRN...
Source: Current Topics in Medicinal Chemistry - October 30, 2009 Category: Chemistry Authors: Okuda T, Kawaguchi Y, Okamoto H Tags: Curr Top Med Chem Source Type: journals

Phosphorothioate-stimulated uptake of siRNA by mammalian cells: a novel route for delivery.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The efficient delivery of biologically functional short interfering RNA (siRNA) in vivo remains a widely unresolved technical problem in therapeutic drug development. The repertoire of concepts for the cellular uptake of oligonucleotide-based tools and drugs has been extended by the mechanistically novel finding that phosphorothioate (PS)-modified single-stranded oligodeoxyribonucleotides (ON) promote the intracellular accumulation of naked extra-cellular siRNA in a variety of cell types. This mode of delivery gives rise to substantial intracellular amounts of siRNA, up to 10(4) siRNA molecules per cell. Conversely, th...
Source: Current Topics in Medicinal Chemistry - October 30, 2009 Category: Chemistry Authors: Detzer A, Sczakiel G Tags: Curr Top Med Chem Source Type: journals

Systemic delivery and quantification of unformulated interfering RNAs in vivo.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Synthetic small interfering RNAs (siRNAs) open promising new therapeutic perspectives in acute and chronic pathologies. A number of experiments in mice demonstrated the ability of naked siRNAs injected under a normal pressure to trigger gene silencing in vivo, translating into a measurable phenotype. We focus in this review on the information that we can gain from these experiments, and discuss how the specificity of the gene silencing in vivo can be controlled. Because the activity of most drugs increases with the dosing, we are prone to consider that increasing the concentration of siRNAs within cells enhances the ef...
Source: Current Topics in Medicinal Chemistry - October 30, 2009 Category: Chemistry Authors: Morin A, Gallou-Kabani C, Mathieu JR, Cabon F Tags: Curr Top Med Chem Source Type: journals

Lentiviral delivery of RNAi effectors against HIV-1.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
RNA interference (RNAi) holds great promise as gene therapy approach against viral pathogens, including HIV-1. A specific anti-HIV-1 response can be induced via transfection of synthetic small interfering RNAs (siRNAs) or via intracellular transgene expression of short hairpin RNAs (shRNAs) or microRNAs (miRNAs). Both targeting of the viral mRNAs or the mRNAs for cellular co-factors that are required for viral replication have been shown successful in suppressing HIV-1 replication. However, like conventional mono-therapies, the use of a single anti-HIV-1 RNAi inducer results in the emergence of RNAi-escape mutants. To ...
Source: Current Topics in Medicinal Chemistry - October 30, 2009 Category: Chemistry Authors: Liu YP, Berkhout B Tags: Curr Top Med Chem Source Type: journals

The therapeutic potential of cell-internalizing aptamers.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Aptamers that are evolved by the SELEX procedure (Systematic Evolution of Ligands by Exponential enrichment) can specifically recognize and tightly bind their cognate targets by means of well-defined secondary and three-dimensional structures. In comparison to antibodies, nucleic acid-based aptamers offer some exciting advantages, including the potential for chemical synthesis, convenient modification, chemical versatility, stability and lack of immunogenicity. During the past 20 years, aptamers have been developed for various applications such as diagnostics, drug development, target validation and therapeutics. Aptam...
Source: Current Topics in Medicinal Chemistry - October 30, 2009 Category: Chemistry Authors: Zhou J, Rossi JJ Tags: Curr Top Med Chem Source Type: journals

Assays for Identification of Hsp90 Inhibitors and Biochemical Methods for Discriminating their Mechanism of Action.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The Hsp90-dependence of many oncogenic proteins has precipitated a great deal of interest in Hsp90 as a drug target, as evidence mounts that Hsp90 inhibitors may be effective chemotherapeutic agents for the treatment of cancer. In addition, Hsp90-inhibitors have shown promise for the treatment of neurodegenerative diseases characterized by the accumulation of toxic denatured protein aggregates. The development of assays for the identification of novel Hsp90 inhibitors began in earnest when it became apparent that the Hsp90 inhibitors available at the time had less than ideal pharmacological properties. This review summ...
Source: Current Topics in Medicinal Chemistry - October 28, 2009 Category: Chemistry Authors: Matts RL, Manjarrez JR Tags: Curr Top Med Chem Source Type: journals

Update on Hsp90 Inhibitors in Clinical Trial.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Twenty-five years ago the first small molecule inhibitors of Hsp90 were identified. In the intervening years there has been dramatic progress in basic scientific understanding of the Hsp90 chaperone machinery and in the role of Hsp90 in malignancy. The first-in-class Hsp90 inhibitor 17-AAG entered into Phase I clinical trials in 1999. There are now 13 Hsp90 inhibitors in clinical trial, representing multiple drug classes, and hundreds of patients have been treated in adult oncology and pediatric oncology trials. This review will provide an overview of the clinical trial results thus far. In addition, pivotal issues in ...
Source: Current Topics in Medicinal Chemistry - October 28, 2009 Category: Chemistry Authors: Kim YS, Alarcon SV, Lee S, Lee MJ, Giaccone G, Neckers L, Trepel JB Tags: Curr Top Med Chem Source Type: journals

Alternate Strategies of Hsp90 Modulation for the Treatment of Cancer and Other Diseases.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The 90 kDa heat shock protein (Hsp90) has become a validated target for the development of anti-cancer agents. Several Hsp90 inhibitors are currently under clinical trial investigation for the treatment of cancer. All of these agents inhibit Hsp90's protein folding activity by binding to the N-terminal ATP binding site of the Hsp90 molecular chaperone. Administration of these investigational drugs elicits induction of the heat shock response, or the overexpression of several Hsps, which exhibit antiapoptotic and pro-survival effects that may complicate the application of these inhibitors. To circumvent this issue, alte...
Source: Current Topics in Medicinal Chemistry - October 28, 2009 Category: Chemistry Authors: Brandt GE, Blagg BS Tags: Curr Top Med Chem Source Type: journals

Purine-Scaffold Hsp90 Inhibitors.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Hsp90 is a molecular chaperone with important roles in regulating the function of several proteins with potential pathogenic activity. Because many of these proteins are involved in cancer and neurodegenerative promoting pathways, Hsp90 has emerged as an attractive therapeutic target in these diseases. Molecules that bind to the N-terminal nucleotide pocket of Hsp90 inhibit its activity, and consequently, disrupt client protein function. A number of these inhibitors from several chemical classes are now known, and some are already in clinical trials. This review focuses on the purine class of Hsp90 inhibitors, their di...
Source: Current Topics in Medicinal Chemistry - October 28, 2009 Category: Chemistry Authors: Taldone T, Chiosis G Tags: Curr Top Med Chem Source Type: journals

Hsp90 Inhibition with Resorcyclic Acid Lactones (RALs).Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Heat shock protein 90 (Hsp90) is an ATP-dependent chaperone which is involved in the post-translational maturation and stabilization of over one hundred proteins ("its clients"). In the absence of Hsp90's chaperoning, its clients are misfolded and degraded via ubiquitin-proteasome pathway. It has become the focus of intense drug discovery efforts as its activity has been implicated in diverse pathologies ranging from oncology to neurodegenerative and infectious diseases. The most promising inhibitors reported to date inhibit the ATPase activity by binding to the N-terminal ATP pocket. Radicicol, a member of the resorcy...
Source: Current Topics in Medicinal Chemistry - October 28, 2009 Category: Chemistry Authors: Winssinger N, Fontaine JG, Barluenga S Tags: Curr Top Med Chem Source Type: journals

Ansamycin Inhibitors of Hsp90: Nature's Prototype for Anti-Chaperone Therapy.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The ansamycin class of natural products is well known for its anti-tumor effects and has been extensively studied by cancer researchers for nearly four decades. The first description of geldanamycin in the scientific literature appeared in 1970 and nearly thirty years later the semi-synthetic derivative 17-AAG, or tanespimycin, entered Phase 1 clinical trials. In the subsequent years, three additional geldanamycin derivatives have entered clinical evaluation. Kosan Biosciences developed 17-DMAG or alvespimycin hydrochloride for clinical evaluation as both an intravenous and oral product. Infinity Pharmaceuticals is dev...
Source: Current Topics in Medicinal Chemistry - October 28, 2009 Category: Chemistry Authors: Porter JR, Ge J, Lee J, Normant E, West K Tags: Curr Top Med Chem Source Type: journals

Structural and Computational Biology of the Molecular Chaperone Hsp90: from Understanding Molecular Mechanisms to Computer-Based Inhibitor Design.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The molecular chaperone Hsp90 (90 kDa heat-shock protein) mediates many fundamental cellular pathways involved in cell proliferation, cell survival, and cellular stress response. Hsp90 is responsible for the correct conformational development, stability and function in crowded cell environments. Structural and computational biology studies have recently provided important insights into underlying molecular mechanisms of Hsp90 function. These developments have revealed a critical role of Hsp90 structure, conformational dynamics and interdomain communication in promoting the binding and release of ligands and its interac...
Source: Current Topics in Medicinal Chemistry - October 28, 2009 Category: Chemistry Authors: Verkhivker GM, Dixit A, Morra G, Colombo G Tags: Curr Top Med Chem Source Type: journals

Strategies for Stalling Malignancy: Targeting Cancer's Addiction to Hsp90.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Hsp90 is involved in the maturation and activation of client proteins. Often these are key proteins involved in signal transduction and regulatory pathways that in a mutated and/or deregulated form sustain an oncogenic cellular state. Consequently, the malignancy is maintained with the aid of Hsp90 upon which the mutated proteins have become particularly dependent for their activity. The requirement for the Hsp90 chaperone machine to drive the malignancy makes Hsp90 a prime anticancer target, an 'axle in a wheel' that when disrupted has been shown to be effective in killing cancerous cells. This review aims to identify...
Source: Current Topics in Medicinal Chemistry - October 28, 2009 Category: Chemistry Authors: Prodromou C Tags: Curr Top Med Chem Source Type: journals

Pharmacological Targeting of the Hsp70 Chaperone.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The molecular chaperone, heat shock protein 70 (Hsp70), acts at multiple steps in a protein's life cycle, including during the processes of folding, trafficking, remodeling and degradation. To accomplish these various tasks, the activity of Hsp70 is shaped by a host of co-chaperones, which bind to the core chaperone and influence its functions. Genetic studies have strongly linked Hsp70 and its co-chaperones to numerous diseases, including cancer, neurodegeneration and microbial pathogenesis, yet the potential of this chaperone as a therapeutic target remains largely underexplored. Here, we review the current state of ...
Source: Current Topics in Medicinal Chemistry - October 28, 2009 Category: Chemistry Authors: Patury S, Miyata Y, Gestwicki JE Tags: Curr Top Med Chem Source Type: journals

Neuron Protection as a Therapeutic Target in Acute Ischemic Stroke.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Involvement of various neurotransmitters and neuromodulators have been shown to contribute to the ischemic injury and neuronal death associated with stroke Role of excitatory amino acid receptor activation, calcium overload, nitric oxide, and oxidative stress in the pathogenesis of ischemic brain damage is well established. Several new strategies are currently emerging, based on recent advances in our understanding of molecular pathways that could be considered as potential therapeutic targets. For example reactive oxygen species (ROS) are important contributors to the secondary injury cascade following traumatic brain...
Source: Current Topics in Medicinal Chemistry - October 22, 2009 Category: Chemistry Authors: Tuttolomondo A, Di Sciacca R, Di Raimondo D, Arnao V, Renda C, Pinto A, Licata G Tags: Curr Top Med Chem Source Type: journals

Antiplatelet Treatment in Ischemic Stroke Treatment.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In this study there was a significant 14% proportional reduction in mortality during the scheduled treatment period (343 [3.3%] deaths among aspirin-allocated patients vs 398 [3.9%] deaths among placebo-allocated patients; 2p = 0.04). There were significantly fewer recurrent ischaemic strokes in the aspirin-allocated than in the placebo-allocated group (167 [1.6%] vs 215 [2.1%]; 2p = 0.01) but slightly more haemorrhagic strokes (115 [1.1%] vs 93 [0.9%]. Few studies examined the role of ticlopidin in acute stroke setting the results showed treatment with ticlopidine improved the neurologic outcome. In the Examining the Safe...
Source: Current Topics in Medicinal Chemistry - October 22, 2009 Category: Chemistry Authors: Pinto A, Di Raimondo D, Tuttolomondo A, Di Sciacca R, Arnao V, La Placa S, Milio G, Miceli S, Licata G Tags: Curr Top Med Chem Source Type: journals

Dyslipidemia as a Risk Factor for Ischemic Stroke.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Ischemic stroke is a major cause of morbidity and mortality. Whereas dyslipidemia is a major risk factor for coronary heart disease (CHD), its role in the pathogenesis of ischemic stroke is less clear. Epidemiological studies have provided conflicting findings regarding the association of dyslipidemia with ischemic stroke. Overall, elevated LDL-C levels appear to increase the risk of ischemic stroke. Low HDL-C levels also appear to be associated with a greater risk whereas the importance of high triglyceride levels is less clear. The discordant results of observational studies might result from the heterogeneity of str...
Source: Current Topics in Medicinal Chemistry - October 22, 2009 Category: Chemistry Authors: Tziomalos K, Athyros VG, Karagiannis A, Mikhailidis DP Tags: Curr Top Med Chem Source Type: journals

Thrombolysis for Acute Ischemic Stroke.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In the last decennium, thrombolytic therapy has changed the management of acute ischemic stroke. Randomized clinical studies have demonstrated that intravenous thrombolysis with tissue plasminogen activator improves functional outcomes. Recently the time window for intravenous thrombolysis has been extended from 3 to 4.5 hours after stroke onset, which will allow more stroke patients to benefit from this treatment. Currently several studies are investigating how to improve recanalization rates of thrombolytic therapy. In this review several aspects of intravenous and intra-arterial thrombolysis are discussed. PMID:...
Source: Current Topics in Medicinal Chemistry - October 22, 2009 Category: Chemistry Authors: Uyttenboogaart M, De Keyser J, Luijckx GJ Tags: Curr Top Med Chem Source Type: journals

Blood Pressure as a Therapeutic Target in Stroke.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Stroke, as a clinical manifestation of the cardiovascular diseases, is one of the leading causes of death and disability in both developed and developing countries. Hypertension is by far, the most important risk factor for stroke. Epidemiological data indicate that the risk of stroke increases with both systolic and diastolic blood pressure elevation, from levels of 115/75 mmHg. It is also evident that most adults worldwide have values above these limits, thus emphasizing the importance of blood pressure as a risk factor for stroke. Clinical trials of antihypertensive treatment, both in studies that have compared acti...
Source: Current Topics in Medicinal Chemistry - October 22, 2009 Category: Chemistry Authors: Armario P, de la Sierra A Tags: Curr Top Med Chem Source Type: journals

Glucose Blood Levels as a Therapeutic Target in Acute Ischaemic Stroke Setting.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Ischaemic stroke is extremely common in western societies contributing to 70-85% of strokes, one of the leading causes of mortality and long-term disability. Despite advancement in preventive measures, the total number of strokes is set to rise in the future due to increasing numbers of aging populations across the world. Diabetes as a risk factor for stroke has been well established. There are also emerging evidence to suggest glucose level management in acute stroke phase as a therapeutic target may be beneficial, albeit remains controversial. One of the issues in difficulty in interpreting study findings is their he...
Source: Current Topics in Medicinal Chemistry - October 22, 2009 Category: Chemistry Authors: Guyomard V, Jamieson EI, Myint PK Tags: Curr Top Med Chem Source Type: journals

Inflammation as a Therapeutic Target in Acute Ischemic Stroke Treatment.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Animal models of focal ischaemia induced by middle cerebral artery occlusion (MCAO) provide most evidence for cellular inflammatory responses in stroke. Permanent MCAO results in a modest neutrophil infiltration at 24 h after ischaemia, predominantly around arterial vessels at the margins of infarction, whereas MCAO with subsequent reperfusion is associated with substantial infiltration by neutrophils throughout the entire infarct. Several studies show that C-reactive protein (CRP), an inflammatory marker, is associated with stroke outcomes and future vascular events. Several drugs, especially hydroxymethylglutaryl coe...
Source: Current Topics in Medicinal Chemistry - October 22, 2009 Category: Chemistry Authors: Tuttolomondo A, Di Sciacca R, Di Raimondo D, Renda C, Pinto A, Licata G Tags: Curr Top Med Chem Source Type: journals

Discovery of Selective Probes and Antagonists for G-Protein-Coupled Receptors FPR/FPRL1 and GPR30.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Recent technological advances in flow cytometry provide a versatile platform for high throughput screening of compound libraries coupled with high-content biological testing and drug discovery. The G protein-coupled receptors (GPCRs) constitute the largest class of signaling molecules in the human genome with frequent roles in disease pathogenesis, yet many examples of orphan receptors with unknown ligands remain. The complex biology and potential for drug discovery within this class provide strong incentives for chemical biology approaches seeking to develop small molecule probes to facilitate elucidation of mechanist...
Source: Current Topics in Medicinal Chemistry - October 6, 2009 Category: Chemistry Authors: Arterburn JB, Oprea TI, Prossnitz ER, Edwards BS, Sklar LA Tags: Curr Top Med Chem Source Type: journals

A Case Study from the Chemistry Core of the Pittsburgh Molecular Library Screening Center: The Polo-like Kinase Polo-Box Domain (Plk1-PBD).Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The Polo-like kinase (Plk) family comprises four cell cycle serine/threonine kinases, Plk1-4. Among these, Plk1 has been most thoroughly characterized; it contains a conserved kinase domain and a C-terminal docking site for S/T-phosphorylated proteins (polo-box domain, PBD). Polo-like kinases are deregulated in oncogenesis and therefore constitute a therapeutic target for cancer. A high throughput screening campaign was carried out by the Pittsburgh Molecular Library Screening Center (PMLSC), using a fluorescence polarization assay with recombinant Plk1-PBD to monitor the inhibition of binding of an optimal phosphopept...
Source: Current Topics in Medicinal Chemistry - October 6, 2009 Category: Chemistry Authors: Wipf P, Arnold D, Carter K, Dong S, Johnston PA, Sharlow E, Lazo JS, Huryn D Tags: Curr Top Med Chem Source Type: journals

The Pilot Phase of the NIH Chemical Genomics Center.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The NIH Chemical Genomics Center (NCGC) was the inaugural center of the Molecular Libraries and Screening Center Network (MLSCN). Along with the nine other research centers of the MLSCN, the NCGC was established with a primary goal of bringing industrial technology and experience to empower the scientific community with small molecule compounds for use in their research. We intend this review to serve as 1) an introduction to the NCGC standard operating procedures, 2) an overview of several of the lessons learned during the pilot phase and 3) a review of several of the innovative discoveries reported during the pilot p...
Source: Current Topics in Medicinal Chemistry - October 6, 2009 Category: Chemistry Authors: Thomas CJ, Auld DS, Huang R, Huang W, Jadhav A, Johnson RL, Leister W, Maloney DJ, Marugan JJ, Michael S, Simeonov A, Southall N, Xia M, Zheng W, Inglese J, Austin CP Tags: Curr Top Med Chem Source Type: journals

Small-Molecule Modulators of the NF-kappaB Pathway Newly Identified by a Translocation-Based Cellular Assay.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Nuclear factor kappa B (NF-kappaB) is an important transcription factor. Aberrant regulation of the NF-kappaB pathway is frequently observed in a number of major ailments such as cancer and inflammatory diseases. Hence NF-kappaB modulators have been intensely pursued for their potential therapeutic applications. Numerous reviews have described recent progress in the development of these agents. More recently, a variety of structurally and functionally novel small molecules, identified through high-throughput screens conducted within the Molecular Libraries Screening Center Network (MLSCN) of the NIH Roadmap for Medical...
Source: Current Topics in Medicinal Chemistry - October 6, 2009 Category: Chemistry Authors: Xie Y, Rinderspacher A, Liu Y, Gong G, Smith DH, Wyler M, Brandén L, Deng SX Tags: Curr Top Med Chem Source Type: journals

The Identification, Characterization and Optimization of Small Molecule Probes of Cysteine Proteases: Experiences of the Penn Center for Molecular Discovery with Cathepsin B and Cathepsin L.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We describe our approach for hit validation, characterization and triage that led to a critical understanding of the nature of hits from the cathepsin B project. In addition, we detail our experience at hit identification and optimization that led to the development of a novel thiocarbazate probe of cathepsin L. PMID: 19807666 [PubMed - as supplied by publisher] (Source: Current Topics in Medicinal Chemistry)
Source: Current Topics in Medicinal Chemistry - October 6, 2009 Category: Chemistry Authors: Huryn DM, Smith AB Tags: Curr Top Med Chem Source Type: journals

Discovery and Development of a Potent and Highly Selective Small Molecule Muscarinic Acetylcholine Receptor Subtype I (mAChR 1 or M(1)) Antagonist In vitro and In vivo Probe.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
This article describes the discovery and development of the first highly selective, small molecule antagonist of the muscarinic acetylcholine receptor subtype I (mAChR1 or M(1)). An M(1) functional, cell-based calcium-mobilization assay identified three distinct chemical series with initial selectivity for M(1) versus M(4). An iterative parallel synthesis approach was employed to optimize all three series in parallel, which led to the development of novel microwave-assisted chemistry and provided important take home lessons for probe development projects. Ultimately, this effort produced VU0255035, a potent (IC(50) = 130 n...
Source: Current Topics in Medicinal Chemistry - October 6, 2009 Category: Chemistry Authors: Weaver CD, Sheffler DJ, Lewis LM, Bridges TM, Williams R, Nalywajko T, Kennedy JP, Mulder MM, Jadhav S, Aldrich LA, Jones CK, Marlo JE, Xiang Z, Niswender CM, Mock MM, Zheng F, Conn PJ, Lindsley CW Tags: Curr Top Med Chem Source Type: journals

Cancer and Virus Leads by HTS, Chemical Design and SEA Data Mining.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
A variety of medicinal chemistry approaches can be used for the identification of hits, generation of leads and to accelerate the development of drug candidates. The Emory Chemical and Biology Discovery Center (ECBDC) has been an active participant in the NIH's high-throughput screening (HTS) endeavor to identify potent small molecule probes for poorly studied proteins. Several of Emory's projects relate to cancer or virus infection. We have chosen three successful examples including discovery of potent measles virus RNA-dependent RNA polymerase inhibitors, development of Heat Shock Protein 90 (Hsp90) blockers and iden...
Source: Current Topics in Medicinal Chemistry - October 6, 2009 Category: Chemistry Authors: Thepchatri P, Min J, Ganesh T, Du Y, Lewis I, Kurtkaya S, Prussia A, Li L, Plemper RK, Fu H, Liotta DC, Snyder JP, Dingledine R, Sun A Tags: Curr Top Med Chem Source Type: journals

Structure- and ligand-based drug design: advances and perspectives.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
PMID: 19754392 [PubMed - in process] (Source: Current Topics in Medicinal Chemistry)
Source: Current Topics in Medicinal Chemistry - September 18, 2009 Category: Chemistry Authors: Andricopulo AD Tags: Curr Top Med Chem Source Type: journals

Docking screens: right for the right reasons?Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Whereas docking screens have emerged as the most practical way to use protein structure for ligand discovery, an inconsistent track record raises questions about how well docking actually works. In its favor, a growing number of publications report the successful discovery of new ligands, often supported by experimental affinity data and controls for artifacts. Few reports, however, actually test the underlying structural hypotheses that docking makes. To be successful and not just lucky, prospective docking must not only rank a true ligand among the top scoring compounds, it must also correctly orient the ligand so th...
Source: Current Topics in Medicinal Chemistry - September 18, 2009 Category: Chemistry Authors: Kolb P, Irwi JJ Tags: Curr Top Med Chem Source Type: journals

Structure-based drug design strategies in medicinal chemistry.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
A broad variety of medicinal chemistry approaches can be used for the identification of hits, generation of leads, as well as to accelerate the development of high quality drug candidates. Structure-based drug design (SBDD) methods are becoming increasingly powerful, versatile and more widely used. This review summarizes current developments in structure-based virtual screening and receptor-based pharmacophores, highlighting achievements as well as challenges, along with the value of structure-based lead optimization, with emphasis on recent examples of successful applications for the identification of novel active com...
Source: Current Topics in Medicinal Chemistry - September 18, 2009 Category: Chemistry Authors: Andricopulo AD, Salum LB, Abraham DJ Tags: Curr Top Med Chem Source Type: journals

Prospective ligand- and target-based 3D QSAR: state of the art 2008.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
As drug discovery and development has grown ever riskier and more expensive, interest has increased in using computational tools to identify good candidates more quickly and to avoid investing resources in synthesizing and testing compounds that are not likely to succeed. The most powerful of these tools seek to exploit the connection between the three-dimensional (3D) structure of a molecule and its various biological activities. Two fundamentally different ways of addressing this challenge have arisen over the years: ligand-based methods that seek to identify and exploit similarities between the structures of ligands...
Source: Current Topics in Medicinal Chemistry - September 18, 2009 Category: Chemistry Authors: Clark RD Tags: Curr Top Med Chem Source Type: journals

Spin-lattice relaxation time in drug discovery and design.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
NMR is one of the most powerful techniques for ligand-biomolecule interaction studies and drug screening and design. There are several methods that are strongly used, including chemical shift perturbation (CSP), saturation transfer difference (STD) and diffusion coefficients. However, one of the most useful and easy to apply NMR parameters in medicinal chemistry studies is the spin-lattice relaxation data, which can be employed to investigate the strength and topology of intermolecular interactions, such as drug-drug, drug-protein, drug-DNA, drug-micelle (or vesicle) and biomolecule-biomolecule interactions. This revie...
Source: Current Topics in Medicinal Chemistry - September 18, 2009 Category: Chemistry Authors: Figueroa-Villar JD, Tinoco LW Tags: Curr Top Med Chem Source Type: journals