MedWorm: Chemists

Nanotech stem cells, order now!

In the Pipeline — Fri, 16 May 2008 12:26:01 +0100

A good rule to follow: hold onto your wallet when two exciting, complicated fields of research are combined. Nature reported earlier this spring on a good example of this, the announcement by a small biotech called Primegen that they'd used carbon nanotubes to reprogram stem cells. (Here's a good article from VentureBeat on the same announcement, and there's an excellent piece on the announcement and the company in Forbes). Stem cells and nanostructures are two undeniably hot areas of research. And also undeniable is that fact that they're both in their very early days - the amount of important information we don't know about both of these topics must be really impressive, which is why so many people are beavering away at them. So what are the odds of getting them to work together? Not as good as the odds that someone thought the combination would make a good press release, I'm afraid. The PrimeGen web site, though a bit better than that VentureBeat article describes it, still has some odd notes to it. I particularly like this phrase: "PrimeGen’s broad intellectual property portfolio is founded on groundbreaking platform technologies invented by our team of dedicated and visionary scientists." Yep, we talk that way all the time in this business. You also have to raise an eyebrow at this part: "Disease and injury applications of PrimeCell™ include Alzheimer’s Disease, Cardiac Disease, Diabetes, Lupus, Multiple Sclerosis, Leukemia, Muscular Dystrophy, Parkinson’s Disease, Rheumatoid Arthritis, Spinal Cord Injury, Autoimmune Disease, Stroke, Skin Regeneration and Wound Healing." It'll mow your yard, too, if you're willing to participate in the next funding round. The next sentence is the key one: "The extent to which stem cells can be used to treat injury and illness has yet to be fully evaluated. . ." You can say that again! In fact, I wouldn't mind seeing that in 36-point bold across the top of every stem cell company web page and press release. But what are the chances of that? As good as the chance that nanotechnology will suddenly going provide us a way to make the stem cells do what we want, I'm afraid. . . (Source: In the Pipeline)

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Hexamine (self-assembly is neat)

Molecule of the Day — Thu, 15 May 2008 14:00:00 +0100

Hexamine is a nitrogenous analogue of adamantane. Read the rest of this post... | Read the comments on this post... (Source: Molecule of the Day)

Copper: a gentleman's disagreement

In the Pipeline — Thu, 15 May 2008 12:28:47 +0100

I was running a copper-catalyzed coupling reaction the other day when my summer intern asked me how it worked. I showed her the mechanism that the authors of the paper had proposed, but pointed out that it was mostly hand-waving. The general features are probably more or less right: the copper iodide presumably does form some kind of soluble complex with the amino acid that’s needed in the reaction mix, and that may well form some sort of complex with the aryl halide, which opens up the ring to nucleophilic substitution, etc. If this were an exam, I’d give full points for that one. But a lot of these couplings are, as I pointed out to her, very hazily worked out. The Ullman reaction, in various forms, has been with us for many decades, and there are more variations on it than you can count. If it always worked reasonably well, or if people had any strong ideas about how it did so, the literature on it wouldn’t be in the shaggy shape it is. Copper chemistry in particular has been (simultaneously) a very useful area for people to discover new reactions, and a horrible trackless swamp for people trying to explain how they work. All you have to do is look at the vicious exchanges between Bruce Lipschutz and Steve Bertz during the 1990s about whether such as thing as a “higher-order cuprate” exists. I have absolutely no intention of reconstructing this argument; I would have to be paid at a spectacular hourly rate to even attempt it. It's enough to say that the arguments raged, in an increasingly personal manner, about what state the copper metal was in, what ligands coordinated to it, and what the active form of these reagents might be (as opposed to what the bulk of the mixture was at any given time). It culminated in what must be one of the most direct titles for a scientific paper I've ever seen: It's on lithium! An answer to the recent communication which asked the question: 'if the cyano ligand is not on copper, then where is it?'. That's in Chemical Communications 7, 815 (1996), if you're interested (here's the PDF for subscribers). Bertz continued to shell Lipshutz's position past the time when any fire was being returned, as far as I can tell, and continues to work in the area. Lipshutz, for his part, hasn't published on the higher-order cuprates in some time (being no doubt heartily sick of the whole topic), but has kept up a steady stream of work on new reactions involving copper, nickel, and other metals. So if well-qualified researchers, brimming with grad students, postdocs, and grant money, can argue for years about copper mechanisms, I'm going to stay out of it. As time goes on, I'm increasingly indifferent to reaction mechanisms, anyway. I want to get product out the other end of the reaction. And while there are times when knowing the mechanism can help reach that goal, those times do not occur as frequently as you might hope. (Source: In the Pipeline)

Adamantane (that's like, what, a million diamonds for $400?)

Molecule of the Day — Thu, 15 May 2008 00:30:23 +0100

Adamantane is a sort of triple-fused-cyclohexane structure: Read the rest of this post... | Read the comments on this post... (Source: Molecule of the Day)

Summer student time

In the Pipeline — Wed, 14 May 2008 12:33:18 +0100

I have a summer intern this year, and she has (so far) not caused anything to burst into flames. That’s the first thing you ask of a summer student, and the fact that she’s gotten several reactions to work is just a welcome extra. A summer with no laboratory bonfires will be a successful summer, as far as I’m concerned. That’s because I’ve experienced the alternative, as I’ve detailed here before. If most of the lab fire stories you hear start out with the phrase “We had this solvent still. . .”, the rest of them all seem to begin with “We had this summer undergrad student. . .” (You can imagine the flame-filled end to any story that starts out with a summer student distilling some solvent – that Venn diagram leaves you with no way out at all). No, after watching an undergrad next door to me kick a four-liter jug of pyridine all over the floor, causing a shimmering wave of unspeakable pyridine vapors to almost knock me off my feet. . .and after watching another one walk away for two hours after setting up a reduced-pressure DMSO still, which inadvertently turned into a high-pressure apparatus and blew DMSO and calcium hydride all over the inside of a hood. . .and after watching them charcoal reactions by plugging heating apparatus straight into the wall outlet instead of into the Variac. . .and, well, you get the idea. I should add that I was no great shakes as a summer undergrad myself. I did a summer after my sophomore year with Tom Goodwin, but didn't get a great deal accomplished (through no fault of his!) Then after my junior year, I worked with Dale Boger, back when he was at the University of Kansas, but I mostly (and rather slowly) found a list of conditions that don't work for inverse electron demand Diels-Alder reactions. But although I spilled some generous amounts of solvent, I didn't set anything on fire. No, we're going to have a calmer and more productive summer around here. I have my student working on a problem I've had a longstanding interest in, one that needs some variables chased down and figured out. With any luck, enough data will be generated to make for an interesting publication late in the year, and everyone will come out ahead. (Source: In the Pipeline)

In which i hate a wonder drug

In the Pipeline — Tue, 13 May 2008 12:32:55 +0100

Schering-Plough has had its share of troubles over the years, but the company has also seen itself saved by some pretty unlikely compounds. Vytorin (ezetimibe) is the example I’ve spoken about here, and if the drug doesn’t seem like a savior at the moment, well, you have to keep in mind that it was the biggest thing for them since Claritin went off-patent ten years ago. Now there’s another one potentially coming up. Expectations are building for a thrombin receptor antagonist compound, SCH 530348. And I have a history with this one, too: while the labs down one hallway from me were discovering ezetimibe, down the other hallway they were laying the foundation for this one. There’s a big difference, though, in the way I saw the two. This thrombin antagonist is an unlikely drug for several reasons. For one thing, its structure is not the sort of thing most medicinal chemists would go out of their way to make. But there’s a good reason for that: to a first approximation, it wasn’t made with medicinal chemistry in mind. 530348 is based on a natural product called himbacine, whose fame, such as it is, rests on its properties as a semi-selective muscarinic antagonist. And that’s how Schering-Plough got interested in this class of compounds; thrombin had nothing to do with it. At the time (early to mid 1990s) the company had a team working on Alzheimer’s disease, and I’ll go ahead and mention again that I was one of the people involved. (Five minutes on SciFinder would tell you that, anyway). We were quite interested in selective muscarinic antagonists, particularly for the m2 subtype, and himbacine was at the time one of the more selective compounds with that profile. So one of the group leaders at the company, Sam Chackalamannil, decided to synthesize it and do some SAR around the structure. That was no small undertaking. Himbacine’s not one of the most complex natural products by any means, but it’s no stroll to the beach, either, especially when compared to the usual sorts of drug structures. It took a lot of time, a lot of ingenuity, and (most importantly) a lot of effort to do it. And I. . .well, I thought this was a terrible idea. I really did. By the time himbacine itself got made, the project team had muscarinic compounds that were more selective and more potent (and a lot easier to make, to boot). I would listen to Chackalamannil’s people presenting their long, difficult routes during meetings, and I’d sit there imagining the company going slowly bankrupt if everyone adopted this approach, the revenue slowly sinking as the number of JACS communications rose. I couldn’t see the point, and although I don’t think I ever quite had the nerve to say so to Chackalamannil himself (hi, Sam!), I said it to plenty of other people. So, is it time for me to eat crow? Well, one plateful, at least. Some of the himbacine analogs hit in the high-throughput screen for thrombin activity, to everyone’s surprise, and some further compounds (now shed of their muscarinic activity) were even better. The drug discovery effort culminated in 530548, which now might be about to benefit a huge number of people and make the company a ton of money, if everything goes well. Of course, if these things hadn’t hit in the thrombin assay, I could have remained secure in my opinion. After all, they were never worth very much as muscarinics, as far as I know. (Of course, our muscarinic compounds, in the end, never were worth very much as Alzheimer’s drugs, which is something to keep in mind). So that’s the question: how likely is it for molecules like this to work? It’s very hard to answer that, but given this data point, I guess the answer is “at least a little more likely than I thought”. The very fact that they didn’t look like most other things in the screening deck was probably in their favor. I still think that these compounds were a long shot, but this is a business that lives on long shots. This one came through, and congratulations to everyone involved. (Source: In the Pipeline)

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I’m not going to renew my acs membership

The Chem Blog — Mon, 12 May 2008 18:42:34 +0100

I’m not going to any ACS conferences this year, so there’s no financial reason for me to do it, but more importantly, I’m pretty sick of the ACS. Aside from a few decent reads in C&EN, I can’t help but feel as though I’m getting fucked by those people. Firstly, the membership costs come out of my pocket. Which is fine, since it’s not yet over $100. Local dues and whatnot, it’s about $75 or something, roughly the cost of GROCERIES. And since student stipends are approximately $1000 more a year than the average cost of living (if you pretend the average cost of living was $2000 less than it is) then you can imagine how I might want that week’s worth of food for myself and the lovely Mrs. Finchsigmate. But, what I’m actually protesting, is not the cost of the dues but that the society doesn’t give a fuck about students. For instance, I myself like to read Org Lett, JACS, JOC and Chem Rev. A year’s worth of subscription to those four mags would cost, with my “awesome” member discount, around $2000 a year. WOW. THX ACS! And it isn’t like they aren’t banking off my goddamn name. I’ve been getting offers from Chase credit cards for “Dr. Finchsigmate.” Which is funny, since I’ve never put “Dr.” on any application in my life. I also get “member only” offers for life insurance, banking, etc etc. Coincidently the same offers my wife, who is an elementary school teacher, gets. Hmmm… They sold my name and address to banks to get some scratch, they put ads in everything and fill each conference up with vendors (and charge you to get in). So, fuck ‘em. I don’t want to be a part of any club that I can’t afford to be a member of, even if boss were to pay for it. I don’t really see why I should be bent over and fucked sideways just so I can get a print edition of JACS. I can get SIX subscriptions to the journal Science for the same price. So, if I were you, I’d spread the word of a goddamn ACS boycot until they lower the student cost of print journals. I like to read on the shitter but I’m not going to pay $550 a year for the pleasure. ShareThis (Source: The Chem Blog)

Explaining it all

In the Pipeline — Mon, 12 May 2008 12:56:15 +0100

One of the reasons I starting this blog was that many people I met were interested in my job. Very few of them had ever talked to someone who discovered new medicines for a living, and a surprising number of them (well, surprising to me) had no idea of where medicines came from in the first place. Talking to such folks (interested, but with no particular training in science) gave me some good practice in explaining the work. It helps that the kind of work I do is actually fairly easy to explain. There are a lot of details – as with any branch of science, the closer you look, the more you see – but I haven’t run across any key concepts that can’t be communicated in plain language. (It also helps that medicinal chemistry, as it’s actually practiced, uses an embarrassingly small amount of actual mathematics). The toughest things to deal with are the parts of the field that actually touch on physics and math. My vote for the hardest everyday phenomenon to explain at anything past a superficial level is magnetism. So that means that explaining how an NMR machine works is not trivial. At least, explaining it in a way that a listener has a chance of understanding you isn’t – a while ago, I took up the challenge to try to explain it here in lay terms, and I haven’t done it yet, for good reason. Explaining statistical significance is doable, but going much past that (principal components, the difference between Bayesian and frequentist approaches) takes some real care. And, of course, when you open the hood on chemical reactivity, the mechanisms of bond-forming and bond-breaking, you quickly find yourself in physics up to your armpits. It’s easier to stipulate, openly or by assumption, that there are such thing as chemical bonds, and that some of them are stronger than others. You don’t want to start answering a question about why one group falls off your drug molecule easier than another one does, only to find yourself fifteen minutes later trying to explain the Pauli exclusion principle. Counterproductive. But the basics of medicinal chemistry can be sketched out pretty quickly, which makes some of the more curious listeners wonder, after a while, why we aren’t better at it. The best example I can give them is to advance a quick, hand-waving explanation of, for example, how compounds get into cells. Then I point out that that explanation is unnervingly close to the best understanding we have of how compounds get into cells. The same holds for a number of other important processes, way too many of them. And that's why drug discovery is simultaneously frustrating and fascinating. We know huge numbers of things, great masses of detail that can take years to piece together. And it's not enough. Some of the most important puzzle pieces are still weirdly ill-defined, and there are probably others whose existence we haven't even realized yet. I'd be willing to bet that if you scanned the whole history of pharmaceutical discovery, you'd find people at every point thinking "You know, in any thirty years they should have all this figured out". But the years go by, and they - we - don't. Give it another thirty years, you think? (Source: In the Pipeline)

More on volatile buffers

Molecule of the Day — Sat, 10 May 2008 02:42:56 +0100

Previously I've mentioned triethylammonium acetate, and ammonium carbonate. These are salts formed by mixtures of volatile stuff - triethylamine, acetic acid, ammonia, and carbon dioxide. Awhile ago I made one I hadn't ever made before. Read the rest of this post... | Read the comments on this post... (Source: Molecule of the Day)

Mein kugelrohr

The Chem Blog — Fri, 09 May 2008 20:45:55 +0100

I have a compound that refuses to be pure and I’m thinking about just taking it on impure (it’s about 90% pure). I’ve attempted a couple ways to purify this oil, but nothing really works. Fractional distillation does indeed help, but I’ve gotten to the point where the ratio of impurities no longer changes, which makes me think I’ve got an azeotrope. I’m doing a derivative of the “general” reaction shown below, which is a bit easier to purify. You can imagine columns are worthless, as all the compounds fly right off in pure hexanes, pentanes, pet ethers… nothing works for column conditions. One thing I did try, however, was our Kugelrohr. Now that fucker is sweet (unless you’re trying to purify 17 mL… but whatever). The idea behind the Kugelrohr is that it very quickly (and quite nicely) distills high boiling shit. It does not do so in a manner that is more efficacious than fractional distillation. Don’t let people tell you that. (This being my own limited observation. I was able to get nicer separation on a fractional column filled with glass loops - it just took 6 hours. This did a little worse, but not much, in 30 minutes.) Nevertheless, it does a pretty goddamn good job. Just outside of the picture is a tubing that runs to my pump, so this whole thing is done at high temperatures and under high vacuum. It’s really not so bad. The way the bulbs are arranged is visible to the side there. I fill the bottom one up with about 2 mL of my sample and place it inside that metal cylinder (which is why you only see two bulbs in the picture) to distill the high boiling stuff, leaving the tar that will never come out no matter how hot you get it. Then I drop the temp of the silver cylinder heating element and just shove the second bulb into the heater to distill off the lighter boiling material. This way, I don’t have to break the vacuum and take apart the glassware - I just have to lower the temp, which is nice, but I don’t know if I actually saved myself time doing it that way. So, if you’re ever in a pinch with a vacuum distillation of high temperature oils and need something a little better than a short path and don’t want to sit around for hours while it refluxes you should get yourself a Kugelrohr. ShareThis (Source: The Chem Blog)

Merck bails on natural products

In the Pipeline — Thu, 08 May 2008 12:50:51 +0100

Every few years, you hear talk of a renaissance in natural products-based drug discovery. Well, this news should postpone the next round of optimism for a bit longer: Merck is cutting their natural products program entirely. They've had a long history in that area, but no more. That C&E News item includes an interesting detail: "The company disclosed that it would also be closing its 50-year-old natural products drug discovery operation based in Madrid after a Merck executive inadvertently included the plan in a PowerPoint presentation to an audience that included Merck employees." Smooth move. I'm sure some interesting e-mails were exchanged around Rahway and Madrid after that one. When, when will we get the powerful regulatory oversight of PowerPoint technology that the masses have cried out for these many years? The main thing I remember about Merck's operation in Madrid was when they made a big splash about ten years ago with a weird looking indole/quinone thing that directly activated the insulin receptor. It made the cover of Science and all sorts of press releases, and my biology colleagues starting pestering me immediately. "Hey, you chemists keep saying that there's no point in running a small-molecule screen against the insulin receptor!" Well, as it turned out, we were right. I assured my co-workers on the next floor that the Merck compound was one of the least likely drug candidate structures I'd ever seen, and that I'd be intensely surprised if it went anywhere. In fact, I told them, seeing it on the cover of Science actually decreased the likelihood that it was anything useful. If Merck really had a small-molecule insulin mimetic, I reasoned, the program would be a real stealth bomber, for fear of sending all sorts of other companies into the same chemical space too quickly. This one had all the signs of the people involved saying "You know, the only thing this stuff is good for is getting on the cover of Science" So it proved, eventually. The compounds never went anywhere. It looks like the most recent natural product-derived compound that Merck got onto the market was Cancidas (caspofungin), and that was seven years ago. Mevacor (lovastatin) will stand as the modern high-water mark of Merck's natural product work - presumably from now on. (Source: In the Pipeline)

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Triacetin (always liquid, always semi-edible)

Molecule of the Day — Thu, 08 May 2008 03:04:38 +0100

Triacetin is the glycerol triester of acetic acid: Read the rest of this post... | Read the comments on this post... (Source: Molecule of the Day)

Science by country

In the Pipeline — Wed, 07 May 2008 12:57:48 +0100

Update: here's the map that I was imagining, thanks to Andy in the comments section. It's on the Worldmapper site linked to below, but I missed it while putting the post together. Most of my speculations turned out to be reasonable, although Venezuela (for one) looks a bit better than I thought it would, and Iran looks a bit worse. Africa and the Islamic world are, as hypothesized, almost invisible. I’d like to see a map of the world with country size dependent on the number of scientific publications and patents – perhaps you’d want to use publications per capita, or per educated capita. That's a cartogram, and although there are plenty of interesting ones on the web, I haven't found that one yet. The US would loom large, that’s for sure. Japan might be the most oversized compared to its geography, although Singapore would also be a lot easier to pick out. Western Europe would expand to fill up a lot of space, with Germany, England, and France (among others) taking up proportionally more room inside the region and (perhaps) Spain and Portugal taking up somewhat less. Switzerland would swell dramatically. South America would be dominated, I think, by Brazil, even more than it is on the map. You’d be able to find Argentina and Chile, but I think some other countries (like Venezuela) would dwindle in comparison. Africa, as it does so often in maps of this kind, would appear to have been terribly shrunk in all directions, with a few countries – Egypt, South Africa – partially resisting the effects. Moving on to Asia, India would appear even larger than it is, unless you went for the per-capita measurement to cut it back down a bit, and China would be a lot more noticeable than it was ten (or especially twenty) years ago. Another region that would basically disappear would be the Middle East and most of the rest of the Islamic world. Iran would hang in there, smaller but recognizable, and you’d be able to find Pakistan, too. But the Arab countries (with the minor exception of Egypt) would nearly vanish. The figures from the Organization of the Islamic Conference (the multinational group involved) show that from 1995-2005, the Islamic countries contributed 2.5% of all the peer-reviewed scientific papers. That’s all the more interesting when you consider the amount of potential funding that washes around that part of the world. This disconnect has been noticed by the region’s scientists, as well it might. The OIC has designated a committee of science ministers to help with a multiyear plan for modernizing things, but no one’s sure if any real money will be forthcoming. According to this Nature article (headlined "Broken Promises"), the OIC countries allocate less than 0.5% of their GDP to research and development. Most of the money promised just to fund that science committee never showed up. Lip service is, of course, a feature of politics (and politicians) everywhere, but I don't think I'm out of line if I suggest that it's very close to an art form in that part of the world. And that's a very short-sighted approach. Many of these countries are sitting on huge amounts of money at the moment, which should be invested against the day that their oil runs out (or against the day that the world decides that it's not as desperate for oil as it once was). That latter day will, presumably, be hastened along by the countries who spend more on research. . . (Source: In the Pipeline)

Highlights of research that i missed while bitching about other shit

The Chem Blog — Wed, 07 May 2008 12:50:24 +0100

This isn’t C&E news concentrates, but I want to cram a few in that I missed over the last few months. I’ve read and loved and you’ll love these advances in the field of chemistry: First: DOI: 10.1126/science.1152692. Fucking brilliant piece from the Baker lab representing state of the art fuckability of proteins. The title: “De Novo Computational Design of Retro-Aldol Enzymes” gives you a half assed idea of what’s actually going on. Where the typical “state of the art” to select for proteins that do specific chemistry is to essentially make a fuck-ton of proteins and run them on a specially designed column or do some Systematic evolution of ligands by exponential enrichment. The idea is NOT to go and design an active site of a protein and then cut out the active site of another protein and stick your active site in it to do the chemistry you want it to do. My brief description trivializes the difficulty inherent here and may overstate the utility, but it’s a monumental push forward for protein engeneering that relies not upon random insertions or specific point mutations but de novo design of an active site and then finding a protein that is compatible with it. Second: DOI: 10.1088/1468-6996/9/1/014104. Sir Fraser Stoddart and Bill Goddard collaborated to create one of the most awesome ideas in supramolecular chemistry , which I’ve gushed over here. The paper details the attempt and successful creation of the “quasi-tristable [2]catenane.” Limitations exist in the system and it’s apparent that the design, as it stands, is unlikely to produce the desired results as an unfortunate overlap appears to exist between the absorption and CT bands of the various colored bits, but I’m still undaunted in my interest of a system like this. Finally: DOI: 10.1002/anie.200800891. The prior post makes this next post a bit more apropos. Design of rotaxanes with strong binding interactions necessarily makes “shuttling” them around rather difficult but the synthesis of interlocked molecules nearly necessitates strong interaction between thread and macrocycle to assemble. A Catch 22, as it were. Leigh and Zerbetto have a rather clever hack which is slightly reminiscent of some of Vogtle’s (and Leigh’s own) work, where the macrocycle is used to direct the chemistry that is going to make the rotaxane in the first place, though they use it in a distinctly clever way by exploiting the copper mediated Cadiot–Chodkiewicz reaction. I have pretty high hopes for this sort of thinking in the design of molecular shuttles. These are just a few of the articles I read and found very interesting. If I weren’t so goddamn busy I’d give literature more treatment and limit my fluff posts. But, it’s my blog, so blah. ShareThis (Source: The Chem Blog)

Mplcs for the people pt 2

The Chem Blog — Tue, 06 May 2008 13:14:55 +0100

I had to take a break from writing the supporting info for a paper I’m doing. Multi colored NMRs and J values and ChemDraw and various other spectra are driving me batshit crazy. Here is a quick post to answer some common questions about the MPLC: Q: How many grams can you load? A: As many as you wish. It becomes cumbersome above 10 grams and hardly worth it below 40 mg. I’ve run as little as 10 mg, however, and gotten pretty good separation. Q: Can you do gradients? A: Yes. As stated, the gradients are fully adjustable since it’s very, very ghetto. You have two bottles and one is pulling solvent out of the other. It’s pretty easy math to do on a spreadsheet. Q: How much does it cost, seriously? A: If you buy all new parts (and I mean all new parts, including a brand new fraction collector) you can get away with about $5,000 - half that cost being the fraction collector. Generally you can skimp and save a few here and there and pull it off for about $1500. When I wrote that post, I was referencing prices from two years ago when I built it, so things have naturally gone up. Q: Does it save solvent or silica? A: Not really a solvent saver. I guess, if you’re into recycling solvent it’s easier to do. I do not recycle my solvent, so it saves me nothing in that regard. It obviously saves a shit load of free silica, since I don’t pack my own columns. If you were to, and you packed them correctly, you could run the same columns over and over again saving yourself a lot of silica gel. Q: How do you load? A: Loading is easy. Dissolve your shit up into a syringe and inject it onto the loading column. If your sample is fully dissolved it shouldn’t plug the column up but the beauty of working with this ghetto system, is you can load your sample into the guard column and if you include a bit of dead space above the silica, it doesn’t have to even be soluble in your mobile phase. I.E. dry packing is usually not needed. Not only that, but the guard column keeps nasty shit like dirty used Grubb’s catalyst off your nice column, so it’s a must have. Q:What about air? A: In the solvent? That’s no problem. But in the column, you’ll want to avoid it, but it’s not the end of the world. The pressure will usually squish the air into the solvent but you’ll want to pump all the air out before you begin. That’s pretty intuitive, I’d think. Q: What kind of columns do you recommend? A: I whole heartedly endorse the use of RT Scientific’s packed glass columns. The inital cost is about $100-$200 for smallish columns but the repacking service is cheap and you can run gallons of chloroform and gallons of methanol through them without doing much damage to them. Eventually, even the best packed column dies (especially if you make a habit of cleaning it with methanol). The problem with RT Scientific is that they’re scatterbrained so, while they offer a superior product, they’re not the best at customer service. Otherwise I use ana logix columns (35 micron pore size silica) since they’re consistently well packed and we get a great deal on them. Q: Do you really run one column a month? A: One FLASH COLUMN. I run about two columns a day, sometimes more, depending on what I’m doing. I like to have a full bench. That being said, I take my sweet time running columns. Usually run one during the day and run the other over night. Since it’s automated (with a fraction collector) I’m not really hurried into forcing the shit through the column unless I have to. Most compounds I’ve encountered prefer to take their time on the column and a slow drip produces great separation. That being said, I can crank it up and be done in half an hour - if needed. Obviously, if my ghetto column is running, I can always pack a flash column and run it, so it’s quite possible to separate two things at once. Q: Does it save you time? A: Fuck yeah. Why you would run a flash column when you could do it automated is beyond me. And, even though I like to toot my own horn a bit, I’m not as good at flash columns as my MPLC and I’m not very patient with collecting the test tubes. If I had an auto-TLCer that would be great. Q: What about a UV detector? A: That might be nice and I’ve got the general electronics figured out if I wanted to make one in the machine shop, but I don’t. The UV detector can’t tell me anything about coeluting shit anyway, which is really more important to me, so I’d have to run a TLC anyway. I guess I could rig up a photo diode array… that would be pretty pimp. But that’s just retarded. ShareThis (Source: The Chem Blog)

Alzheimer's: a report from the front

In the Pipeline — Tue, 06 May 2008 12:20:42 +0100

Several recent papers in Neurology offer some interesting ideas on Alzheimer's disease. The one that's getting some headlines today suggests that long-term use of ibuprofen has a protective effect against the disease. Actually, the authors looked at all sorts of non-steroidal antiinflammatory drugs, but the correlation was strongest for ibuprofen. (That may be just because it's used so much, however, and not some intrinsic property of that specific drug). Interestingly, although some NSAIDs have been shown to inhibit formation of beta-amyloid (the protein fragment implicated for many years in Alzheimer's), no particular effect was seen for that class of drugs versus the other NSAIDs. There's long been a suspicion that a lot of Alzheimer's pathology is driven by inflammation cascades, and although evidence has been mixed to date, this would seem to be good evidence for that idea. (More on this in another post). This wasn't a prospective study - they didn't enroll people just to test this idea - but a huge number of VA patients were studied retrospectively, and the authors appear to have done as much as possible to control for other variables. Of course, in an observational study like this one, you can't control for the biggest possible confounding factor: what if there's something about patients who end up taking NSAIDs more often that also keeps them from developing Alzheimer's? That certainly can't be ruled out, but I don't think there's room for that in most of the headlines. It's going to be tempting for worried patients to start taking ibuprofen to prevent dementia - and that just might work, still - but we really can't be sure without plenty of prospective trial data. Of course, not everything is good for preventing Alzheimer's. You can apparently add statins to that list. An examination of aging Catholic clergy (mostly nuns) showed no correlation at all between statin use and the development of the disease. This is one of those long-running studies that ends with death and subsequent brain histopathology, too, so it's pretty hard to argue with. Intellectually demanding work, though, does perhaps show a protective effect. Interestingly, this effect was even stronger in the cohort of patients that scored lower in assessment of overall intelligence, which makes sense in a way. (Cue the arguments about whether general intelligence exists, whether it can be measured, and if so, whether it's being measured in the correct way). On the ever-profitable herbal front, you see all sorts of claims made for Gingko biloba extract and cognitive function, and there are a lot of contradictory studies (many of which, unfortunately, aren't worth much). This latest one won't help much - in the intent-to-treat analysis, no effect was seen. When they controlled for how well patients stuck to the treatment, then some correlations emerged between taking the extract and slower rates of memory loss. Unfortunately, a correlation (at the same level of significance) emerged with stroke and associated TIAs. My prediction: the ginkgo biloba sellers will trumpet the first set of statistics, assuming they need recourse to any data at all, and ignore the second one completely. Such is the current state of Alzheimer's. To be honest, none of these studies (or most of the others in the same issue) would have been out of place back when I was working in the field in the early 1990s. The field awaits its breakthrough, and has been waiting for a long time. . . (Source: In the Pipeline)

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Fmoc (amino acid condoms)

Molecule of the Day — Tue, 06 May 2008 03:30:10 +0100

Automated solid-phase synthesis of biomolecules defines 20th century biology. I previously covered a protecting group that is ubiquitous in DNA synthesis, but the Nobel was actually awarded for peptide chemistry. Read the rest of this post... | Read the comments on this post... (Source: Molecule of the Day)

Naming of names

In the Pipeline — Mon, 05 May 2008 12:23:57 +0100

We order chemicals from all sorts of suppliers – big, reputable outfits like Sigma-Aldrich-Fluka all the way down to places that none of us even have heard of before. In those latter cases, the primary question is always whether or not the reagent will actually show up, and the secondary one is how long it’ll take. There are some of those small suppliers who pad their catalog with things that aren’t exactly available, not yet – but hey, they will be if someone orders them. They’ll just tell you it’s back-ordered, and tell someone in the lab to get cracking. And when you get your compound in, they arrive in various forms. Glass or plastic bottles are the norm, naturally, with the occasional irritating (but presumably necessary) sealed-glass ampoule. But after some time in the lab, you can tell some of the suppliers from across the room. For example, the Japanese company TCI sends a lot of its compounds in normal-looking glass bottles, but these are first put inside capped plastic containers, like larger translucent versions of the ones that 35mm film probably still comes in. And once you taken them out, their glass bottles have these odd plastic labels on them which come up around the screw cap and are perforated around the cap’s border. On the labels, they also have that same thin, fussy, serif font that the Japanese have been using for Roman-style letters for decades (since the war?) and is only in recent years disappearing from their world. Maybridge, British vendor of all kinds of odd stuff, often sends its compounds in these weird little squat brown-glass bottles with small black caps on them. They must have the world supply of that particular bottle shape tied up, since I’ve never seen one anywhere else. It most resembles the small bottles that solutions for injection are packaged in. So many of the company’s catalog items are in such bottles (or even smaller ones) that it seems wrong somehow when you come across a huge (huge for Maybridge) hundred-gram bottle with their label on it. Most of the suppliers have neutral-sounding names like those above. They could be chemical companies, vendors of kitchen cabinets, real estate trusts, who knows: Maybridge, Oakwood, Lancaster (now gone, and their blue labels with them). And some of them are unmistakably in the chemical supply business, but rather blandly named (Pharmacore, for example, or Chembridge). Some names are, perhaps, mistakes: the namers of Asinex, for example, seem to have been unaware that the closest Engish word is “asinine”, which means that they have to hope for people to pronounce that “s” as if it were a “z”. (I should mention that both Asinex and Chembridge indulge in one widely hated practice: putting no useful information on their tiny vials other than a catalog number or bar code – Bionet (Key) is a similar offender). In this dull company, I’m always glad to see the weirdos. I miss the now-purchased-away British supplier called Avocado – green labels, naturally – and always wondered who named them and why. Tyger Scientific makes me wonder if there’s an English major in somewhere at their founding, fond of William Blake. And there’s one company that came into the industry under the glorious name of, I am not making this up, “Butt Park”, and many are the chemists they’ve made stand puzzled in front of the supply cabinet. (I'd provide a link, but I can't find a direct one, and Googling it can be a real minefield). I refuse to consider that name a mistake. That's a feature, not a bug, and I wish that there were more competition in the category. I would proudly and purposely send business to, say, Batshit Chemical Supply, Inc., even if they back-ordered me every single time. (Source: In the Pipeline)

"not useful" means "not approvable", right?

In the Pipeline — Fri, 02 May 2008 12:52:13 +0100

One recent drug industry setback I haven't noted around here - well, OK, to be more specific, it's a Merck setback, and boy must they be getting sick of those - is the FDA's "not approvable" letter for the Singulair/Claritin combination pill. As the folks at the InVivoBlog note, it sure was hard, from one perspective, to see that one coming. After all, Claritin (loratadine) has an exemplary safety record and has been on the market for many years now, and Singulair (montelukast) has been selling in the billions of dollars as a stand-alone drug. No doubt many people have taken, and are taking, the two as separate pills. So you combine them and get a "not approvable": right. The In Vivo people speculated that this might be a safety problem, since the agency has been mighty jumpy about that area recently, but Merck has now told them that safety and tolerability weren't raised in the FDA letter. Well, what does that leave? Manufacturing? Hardly possible, given the way that these two drug substances are already being cranked out. That, as far as I can see, leaves good old efficacy. You could always argue that putting the two compounds into one pill improves patient compliance, etc., if the combination itself is useful in the first place. But in this case, I'd guess that the problem is that the combo has turned out to offer no benefit over either drug taken alone. Hard to make a case under those circumstance, it is. And if you look into the history of a Singulair/Claritin idea, that appears to be just the problem. As the Wall Street Journal's Health Blog notes, the companies had already found no benefit for seasonal allergies, compared to either drug standing alone. Supposedly they were able to come up with some sort of nasal congestion data (what a joy that must be) that showed an edge this time, but yikes - how desperate do you have to be to take things to that point, after you've already seen no benefit in the main endpoints? So why are Merck (and Schering-Plough) spending money on this kind of last-gasp line extension? Surely there are better places to burn cash. I've never been sympathetic to the argument that money spend on promotion is somehow stolen from R&D, but this sort of thing is another matter. Stupid R&D most definitely steals money from smarter R&D, and here's some of it that's made off with the swag. (Source: In the Pipeline)

Dichloromethane (now healthier with 50% less chlorine!)

Molecule of the Day — Fri, 02 May 2008 01:49:53 +0100

Chlorinated solvents are great solvents. The polarizability of chlorine, moderate electronegativity, moderate volatility, lack of acidic protons or reactivity - it all adds up to a great reaction medium. However, they usually are toxic. Read the rest of this post... | Read the comments on this post... (Source: Molecule of the Day)

Mplcs for the people

The Chem Blog — Thu, 01 May 2008 14:00:02 +0100

I don’t like to run columns and I generally don’t. My syntheses are so bad assed, I generally work harder at figuring out purification methods that don’t require silica because columns are very, very wasteful and it hurts the earth and Al Gore’s feewings. That being said, most of my shit is purified on a column. But I’m both smart and lazy so I’ve used technology to make my life 900% easier by running flash chromatography once a month. My other column is a ghetto MPLC and I LOVE IT OMG LOL!!!!1!1one!. An MPLC is the “medium pressure” variant of an HPLC, but they really couldn’t be further from HPLCs. Whereas HPLCs are unmistakably scientific instrumentation, MPLCs never are. They’re simple purification machines and, as such, they shouldn’t cost $6000. (a bargain when you consider the $40,000 an HPLC costs) I provide here the means for you to build your own MPLC for purifying organic goodies for under $1500. If you can’t swing that, you should get another lab. Since I’ve run all kinds of things on this set up, I can promise you that if you can separate it on a flash column, you can separate it better on an MPLC. I list vendors here, but you can buy from anyone. These are just the guys I buy from and I’m not getting any money by mentioning their names (though I should) so I can be candidly honest about all of them. MPLCs can be divided up into 3 parts: The part that runs the solvent, the place where your shit is separated and the part that collects the solvent as it comes off the column. The first thing you need to consider is a pump and a solvent system. I run a lot of binary gradients, but that doesn’t mean I need to buy two pumps. All it means is I need to buy two bottles, one of which has an awesome screwcap top. The pump I have connected it to is an FMI “Q” Pump. You can find out more about these guys here at their website. The pumps can produce a lot of pulsation, but that’s taken care of down the line. This pump is a cheap one and I’ve let it run dry over a weekend and it still keeps chugging. It’s grade A good shit. The whole thing is about $500. You can control the flow rate by twisting a little knob. It not only gets pretty fast, but you can even make it go backwards, which I have yet to find a use for. That bottle is obviously from an Acros bottle and that PFTE cap was purchased from RT Scientific. Essentially, as a vacuum is created in the brown bottle, it pulls solvent from the clear bottle. This is how I get my gradient. It’s very much a true gradient - as much so as a 50mL prep HPLC binary system can produce. That silver thing the brown bottle is sitting on is an old shitty stir plate, of which most labs have a shitty one lying around. That’s the first part. The second part involves the actual purification and sample introduction. That’s actually even cheaper. As you need to purchase an $8 disposable column from Ana-logix (you can ask for a free sample pack from a sales rep), a $30 gas tight syringe, a $70 3-way lure lock and a small glass loading column, also available from RT Scientific for something like $100. The whole assembly is connected with about $20 worth of tubing and I’ve run more than 300 liters of chloroform (seriously) through this set up. Nothing will touch it. The pulse suppressor is probably necessary. You can buy it from FMI (see that link above) for something like $250. That’s a lot of money, but separation is generally unaffected if you keep the pump speed low. If you can afford it, get it. So, that’s pretty much all you need if you want to collect by hand and you’re still under $1000. Collecting by hand is awfully gay and sort of defeats the point of “automation” since I find nothing more enjoyable than setting up my MPLC and going out to lunch or writing a blog post (the MPLC is indeed pumping as I write this). But this isn’t such a big deal. While fraction collectors are notoriously over priced, Ebay always has good deals on them. Indeed, a quick search turned up 66 different items. The best part is, if you pay for it with your own money you can tell people to fuck off if they want to use it and you can take it with you to your next job/postdoc/whatever. I didn’t have to buy my own, but life without it would be the sucks. Indeed, here is an Ebay store selling the older version of what I’m using right now for only $250. So, there you have it. Automated for under $1200. You can think of it in terms of saving money in solvent and silica (you won’t) or think of it in terms of saving time. Now… you could be asking yourself “But Kyle, you’re rich and famous. Why are you using such a ghetto-assed-fuggly MPLC set up like that?” To which I would respond: Because. I built it from NOTHING AND MADE IT PERFECT. And no one will use something that looks like a bunch of shit hobbled together so I pretty much get it 100% of the time, even though it kicks so much ass its feet are forever covered in shit. ShareThis (Source: The Chem Blog)

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O pioneers!

In the Pipeline — Thu, 01 May 2008 12:26:00 +0100

Drug Discovery Today has the first part of an article on the history of the molecular modeling field, this one covering about 1960 to 1990. It’s a for-the-record document, since as time goes on it’ll be increasingly hard to unscramble all the early approaches and players. I think this is true for almost any technology; the early years are tangled indeed. As you would imagine, the work from the 1960s and 1970s has an otherwordly feel to it, considering the hardware that was available. And that brings up another thing common to the early years of new technologies: when you look back on them from their later years, you wonder how these people could possibly have even tried to do these things. I mean, you read about, say, Richard Cramer establishing the computer-aided drug design program at Smith, Kline and French in nineteen-flipping-seventy-one, and on one level you feel like congratulating his group for their farsightedness. But mainly you just feeling like saying “Oh, you poor people. I am so sorry.” Because from today's perspective, there is just no way that anyone could have done any meaningful molecular modeling for drug design in 1971. I mean, we have enough trouble doing it for a lot of projects in 2008. Think about it: big ol’ IBM mainframe, with those tape drives that for many years were visual shorthand for Computer System but now look closer to steam engines and water wheels. Punch cards: riffling stacks of them, and whole mechanical devices with arrays of rods to make and troubleshoot stiff pieces of paper with holes in them. And the software – written in what, FORTRAN? If they were lucky. And written in a time when people were just starting to say, well, yes, I suppose that you could, in fact, represent attractive and repulsive molecular forces in terms that could be used by a computer program. . .hmm, let’s see about hydrogen bonds, then. . . It gives a person the shudders. But that must be inevitable – you get the same feeling when you see an early TV set and wonder how anyone could have derived entertainment from a fuzzy four-inch-wide grey screen. Or see the earliest automobiles, which look to have been quite a bit more trouble than a horse. How do people persevere? Well, for one thing, by knowing that they’re the first. Even if technology isn’t what you might dream of it being some day, you’re still the one out on the cutting edge, with what could be the best in the world as it is. They also do it by not being able to know just what the limits to their capabilities are, not having the benefit of decades of hindsight. The molecular modelers of the early 1970s did not, I’m sure, see themselves as tentatively exploring something that would probably be of no use for years to come. They must have thought that there was something good just waiting right there to be done with the technology they had (which was, as just mentioned, the best ever seen). They may well have been wrong about that, but who was to know until it was tried? And all of this – the realizations that there’s something new in the world, that there are new things that can be done with it, and (later) that there’s more to it (both its possibilities and difficulties) than was first apparent – all of this comes on gradually. If it were to hit you all at once, you’d be paralyzed with indecision. But the gap in the trees turns into a trail, and then into a dirt path before you feel the gravel under your feet, speeding up before you realize that you’re driving down a huge highway that branches off to destinations you didn’t even know existed. People are seeing their way through to some of those narrow footpaths right now, no doubt. With any luck, in another thirty years people will look back and pity them for what they didn’t and couldn’t know. But the people doing it today don’t feel worthy of pity at all – some of them probably feel as if they’re the luckiest people alive. . . (Source: In the Pipeline)

How not to do it: diazomethane

In the Pipeline — Wed, 30 Apr 2008 12:22:13 +0100

This post will have one of those stories that I can’t vouch for personally, and I’m very glad of that. It involves making diazomethane, which will have already gotten the attention of the chemists in the crowd. Diazomethane’s a very useful reagent, but it has to be treated the right way. You can’t buy it – no one will ship the stuff – so you have to make it fresh. (There are several such reagents). For many years there have been chemicals in the catalogs whose only real use has been to generate diazomethane when needed. Generally this involves treating some nasty N-nitroso compound with base in ether, then distilling over the ether solution of the reagent, which is a distinctive bright yellow. There’s where some of the trickiness comes in. That diazo group is looking for an excuse to revert back to nitrogen gas, which process comes with an inevitable no-substitutions side order of kaboom. The chemist’s job is to not give it that excuse. That means that you can’t heat the stuff up, you don’t make it very concentrated, and you don’t even expose it to sharp or rough surfaces, because that can be enough right there. They sell distillation glassware specifically for diazomethane preps, with weirdly glossy ground-glass joints. You can keep your yellow solution stockpile in the freezer for a while, and the temptation is always to make a lot of it so you never have to do it again. That leads to phenomena like the big flask of the stuff left behind when someone leaves the grad school group. One of those surprises (“Is this yellow stuff what it looks like it is? How long has it been in here? And who the hell made it, anyway?”) was the cause of a new lab inspection requirement while I was getting my degree. You couldn’t leave until someone determined that you weren’t passing on any explosive bequests. Of course, sometimes you honestly need a lot of these things. One of the guys in my group was in that situation early in his total synthesis. One summer afternoon, the power went out in the labs during a thunderstorm, and the head of our safety committee came rolling a big cooler of dry ice down the hall. “Anybody need to store something in the cold?” was the call. “Well,” I said, “we’ve got a couple of liters of diazomethane solution.” “That’s not very funny,” he said. “That’s because it’s not a joke”, I replied, and we moved to the front of the line. So, what’s the stupidest way to handle the stuff? That’s the story told to me by a colleague. He attests that when he was in grad school, he looked across the hall to see someone involved in making a goodly amount of diazomethane – in a large standard ground-glass-joint apparatus. Oh, dear. How the guy was going to get his collection flask off without running the risk of grenading everything, that was the question. As my friend watched in disbelief, the guy reached up to just twist the darn thing right off. . .and it was stuck. A frozen joint – just the perfect time for it. (This is the point where the audience for this story began to bury their heads in their hands). My colleague swears that he then watched this maniac pick up a propane torch to sweat the joint loose. I believe that someone may have stopped him in time, but I think the teller of this tale decided to adjourn for lunch at some distant location right around then, so I can’t vouch for the outcome. But if anyone has a more drooling, slack-jawed approach to an ether solution of diazomethane than running a propane torch over it, I’d like to know what it is. Short of maybe using it as an HPLC solvent, I’m out of ideas. (Source: In the Pipeline)

Cordaptive q and a

In the Pipeline — Tue, 29 Apr 2008 12:18:27 +0100

So why is Merck's stock dropping - again? The FDA just unexpectedly handed them a "not approvable" letter for their latest drug, Cordaptive. Actually, we should stop calling it that, since they also told the company that they're not going to approve that name, either. What Merck's going to do with all their promotional freebies now, I can't imagine. What's Cordaptive, or whatever it's called, anyway? That's Merck's newest cardiovascular drug - although the active ingredient isn't new. It's niacin, also known as vitamin B3. It's been known for many years that niacin can both lower LDL cholesterol and raise HDL, as well as lowering triglycerides - in fact, it's probably one of the only things that can do all of those significantly at the same time. So this is a rip-off, then? Merck's trying to sell vitamin B for $20 a pill? No, it actually isn't, at least not to the extent you're thinking. The problem with niacin as a cholesterol therapy is that you have to take whopping amounts of it to see an effect. And there's a side effect - flushing of the face, which is basically uncontrollable blushing that can last for hours in some cases. That may not sound like much, but the great majority of people who take niacin at these levels have a problem with it, and a lot of people discontinue the therapy rather than put up with it. If the drug is taken for a few weeks, the flushing reportedly eases off some, but not everyone makes it to that point. By all reports, it's very irritating - and since patients can't feel their cholesterol being high, but can feel their faces burning and turning red, they solve the problem by not taking the niacin. So why doesn't Cordaptive do the same thing? A lot of people have tried to find a way to keep the lipid effects of niacin and get rid of the flushing. Merck added a prostaglandin receptor antagonist, laropiprant, to try to block the pathway that leads to the vascular effects. And it seems to help quite a bit, which made the combination a potential winner. Abbott already has Niaspan, a slow-release version of niacin, which also has reduced flushing problems and does about $600 million of sales a year. Niacin therapy itself seems to be pretty safe, although you do want to make sure that liver and kidney function are normal before you start, so the only big question has been what blocking that DP1 receptor might do on the side: can you take that pathway out without causing more trouble? Well, can you? Apparently not. Actually, that should be "apparently there isn't enough evidence to say yet" - that's probably more in the spirit of the FDA's letter. They want to see more information about the drug. Problem is, the FDA treats this (properly) as a matter between the agency and the drug company, so they aren't saying what the problem is. And Merck, for its part, isn't saying, either. Investors feel rather left out in these situations - perhaps the most striking one in recent years was Sanofi-Aventis's absolute wall of silence for months about why the FDA wasn't approving their potential blockbuster Acomplia (rimonabant). Why's this so unexpected, if there wasn't enough evidence given to the FDA? Well, there seems to have been enough evidence in the same pile of data for the European Union, whose regulators approved the drug a few days ago. Merck must have felt reasonably confident that they'd get the same treatment here. No such luck. And as just mentioned, we don't know if the problem is not enough evidence of efficacy, not enough evidence of safety, or a bit of each. Why don't you people just make cholesterol-lowering drugs that work better, then, so there's no doubt about efficacy? Would that we could. Statins basically only lower LDL - they don't raise your HDL. And if you push the statins too hard, patients start coming down with rhabdomyolysis, and you don't want that - ask Bayer. Raising HDL has proven to be a real challenge, too. There are a lot of ideas about how to do it, but the most obvious ones aren't working out too well - ask Pfizer. OK, then, why don't you just make safer versions of what you already have? Would that we could. But in almost every case, we have no idea of how to do that. For the most part, either the safety concerns are tied up with the beneficial mechanism of the drug, or they're occurring through side pathways that we don't understand well and don't know how to avoid. And some of those are things that you don't even get a read on until your drug gets out into the market, which is no way to do things, either. So, why is the drug business considered such a safe bet? Now, that one I don't have an answer for. Unless it's the conviction that people are always going to get sick, which I guess is a pretty safe bet. And that's coupled with a conviction, apparently, that we're always going to be able to do something profitable about that. And some days, I have to wonder. . . (Source: In the Pipeline)

Niacin (nicotine vitamins?)

Molecule of the Day — Tue, 29 Apr 2008 03:20:50 +0100

Niacin is also known as Vitamin B3. Interestingly, it's also called "nicotinic acid," and the similarity of the name to "nicotine" isn't coincidental: Read the rest of this post... | Read the comments on this post... (Source: Molecule of the Day)

A salute

In the Pipeline — Mon, 28 Apr 2008 12:25:42 +0100

Dr. Warfield Teague is retiring this year, which makes me feel old. He was one of the professors who helped make me what I am today – in his case, partly by keeping me out of his chosen field of inorganic chemistry. It was a good move on his part; I’d surely have blown something up good and thoroughly when I got to grad school, such are the opportunities in that area. Unfortunately for both him and for me, his Advanced Inorganic course ended up scheduled for 7:40 AM back in early 1983. I started out my college career with a barrage of classes at that hour, and made every one of them. My sophomore year, I only skipped one class, and I waited for the lightning bolt to descend even for that one. But my junior year I had a professor or two whose lectures could be safely (even profitably) missed, and I began to get in the habit. Teague wasn’t in that category, though. His lectures were fine; it’s just that they took place so early in the morning. My roommate David and I, both chemistry majors, found it harder and harder to summon the activation energy needed to make it out of the thermodynamic sinks of our beds. Dr. Teague’s threat to come over and teach the class in our dorm room didn’t quite do the trick (while lying there in bed, actually, the idea had a certain appeal). But his threat to start giving top-of-the-morning quizzes did. I showed up, and kept showing up. First year of grad school, now that’s where I started slacking off in my classes in earnest. But not all of the professors I had that year could communicate the facts of their specialty as well as Dr. Teague could for his. The lab part of the course, that I would have shown up at 6 AM for. I don’t know how he’s done it in recent years, but 25 years ago (not possible, that), we could do pretty much any lab procedure that Dr. Teague would sign off on. There was a requirement that we do at least one low-temperature one, one high-temperature one, one metal complex, and so on. So the dozen or so of us in the class would root around through Inorganic Syntheses or the like, looking for interesting stuff. And there’s plenty of it in there, let me tell you. In my case, the most memorable included the preparation of fluorosulfonic acid from scratch. Scratch means you start from concentrated hydrofluoric acid, a fine substance for the spirited undergraduate chemist to become familiar with. I can still hear the peculiar whine that solid KOH pellets make when you toss them into a plastic dish of the acid – they’ve a pretty short half-life in there, I can tell you. And I also made the magnesium analog of ferrocene – magnecene, I guess you’d call it – by one of those don’t-be-afraid-of-the-obvious routes: heat some magnesium turnings to about 600 C in a tube furnace, and pass fresh cyclopentadiene monomer vapors over them. Works great. And while you shouldn’t be afraid of the paper synthesis, red-hot magnesium metal is something else again. While I was thus engaged, my classmates were setting off thermite reactions, making phosgene from carbon tetrachloride (chromium trioxide, five hundred degrees, nothing to it), and preparing titanium tetrachloride from the ground up. (I can’t recommend that particular prep – the liquid “tickle-four” comes out bright green from being around 1 molar in dissolved chlorine gas, so you’re going to want to redistill it, most likely). We learned a fair amount of inorganic chemistry, and more than a fair amount of lab technique. As evidence for that, we all survived. Whether the latest generation of undergrads will get these kinds of experiences, I don't know. But I'm glad I did, and I'd like to thank Warfield Teague for providing them. (Source: In the Pipeline)

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There is clearly a wall between us

The Chem Blog — Mon, 28 Apr 2008 03:48:02 +0100

I don’t want anyone taking the impression that I, Kyle muthafuckin Finchsigmate, am in any way disparaging those who do natural product total synthesis. You may have gotten that since sometimes people read comments and attribute them to the post author and, well, it confuses some people even more. I am not opposed to TS research. But… there are two generalizations about TS that I want to expel. Firstly, structural conformation is necessary by total synthesis and drug targets are often inspired by the complex structures of mother nature. You’ve got to do one to get the other. Secondly, it’s a good place to test new catalysts and methodology. The point of many papers in TS, in fact, appears to be to demonstrate some minutia of chemical intuition is correct under the guise of a giant molecule rather than to set out to make a giant molecule with the ancillary hope that you prove that some minutia of chemical intuition is correct. A bonus third reason is, to develop a synthetic pathway that was flexible so that derivatives could be formed at specific positions - objective more easily done inside a total synthesis lab. It is frustrating that none of these points were raised in the keyboard gnashing in the last post. A lot was said about the need to “train organic chemists” which isn’t a reason to fund TS but it’s a good reason to do it - a chemist who does nothing but attempts to synthesize the hardest compound they can is likely most qualified to produce compounds for drug testing (though this isn’t necessarily always true.) There was one misguided attempt at claiming certain organometallic reagents originated with TS, but tripping over the first hurdle out of the gate pretty much ends the race. Still I give that person credit for trying. If there is one stereotype about TSers that needs to be addressed it’s that they have no idea why they’re doing what they’re doing. Of all the stereotypes, I encounter that one more often. On the other hand, there was a lot of name calling and vitriol reserved for TSers, namely for their arrogance. This is a stereotype which lacks true self analysis. I can think of a few of the most arrogant people I know in my department and, to be honest, I can think of only one that I find repulsively arrogant in total synthesis. The rest are in various other groups doing various other things (even BIOCHEMISTRY!). The distribution is pretty broad. But, as I leave at night, when I look back at the building - most of the labs are dark. The biochemists are clearly gone, the inorganic chemists and computational chemists all have their lights out, indeed, the only lights in the building that remain on are those of the labs that do organic synthesis (including my own). So maybe that sleep depraved determination gives them some legitimacy? I don’t know. I think my point is, everyone should get out of their labs and walk over to meet other people who do other work or make an effort to read outside your field or go to seminars that aren’t related to what you do. Have the balls to ask a question. I’ll be honest with you I’ve asked some pretty retarded questions in seminar but I don’t give a fuck. They sounded good in my head and I’ve gotten to be WAY too cynical about the notion of “intelligence” to care what other people think of mine. The only way you’ll ever know is if you ask and the only way you’ll ever ask is if you build up the nuts to do so ShareThis (Source: The Chem Blog)

Why buy, anyway?

In the Pipeline — Fri, 25 Apr 2008 12:47:23 +0100

I don’t want to say that this is a trend, but I notice that GSK is saying that they’re going to leave Sirtris more or less alone as well (as Takeda has said they’ll do with Millennium). The researchers in both shops should feel good about that, and not only because they’ll be keeping their jobs. They’re getting a vote of confidence in the most meaningful way that a large company can give that to its employees: by paying you money and not messing with you. Of course, these deals have two sides to them. I don’t know what it’s like in Takeda back in Japan – my contacts inside the Japanese pharmaceutical industry aren’t extensive. But I think that some of the people at GSK (where I do know a lot of people) are wondering just what motivated their company to spend $720 million on Sirtris rather than on them. It’s a fair question, even though I don’t have a problem myself with the Sirtris deal (as I said yesterday). But the sirtuins themselves are targets that anyone can work on, and you’d assume that a big outfit like GlaxoSmithKline could, if they wanted to, make a big push into the area and find some interesting things. So why didn’t they? The most obvious reason would be Sirtris had already done a good deal of that work, and it was more economical for GSK to buy it than to redo it. Another possibility is that the chemical space for drug-like hits in that area may not be very spacious, and that Sirtris may have already carved out a good piece of that real estate. There’s also a bit of Glaxo history to deal with. The company had already, about fifteen years ago, decided to make a great big push into a promising new research area: nuclear receptors. They set up a whole research institute and did a huge amount of good science trying to figure out how these things worked, what they were good for, and how to get drugs that affected them. I got interested in the field in the late 1990s, and it became clear to me very quickly that Glaxo’s effort was the most serious of the bunch (and that included some really substantial research going on at Merck, Lilly and some other outfits). The company had teams of people who seemed to do nothing else than study the structures of these things, generate reams of X-ray data, synthesize huge lists of ligand molecules of every kind you could want, and so on. Just run "Glaxo nuclear receptor" through PubMed to see what I mean. And what did it get them? From what I can see, not much. Avandia (rosiglitazone) is a nuclear receptor ligand (for PPAR-gamma), but its activity had already been discovered, and it was in clinical trials without a known mechanism. Figuring out how it worked was one of the Glaxo team’s early triumphs. But Avandia has turned out to be famously troublesome, and no others have come to market, despite multiple tries in the clinic. The huge amount of time and money the company spent generated a lot of interesting science, but appears (at least to me) to have brought in not one dime of revenue. (No doubt someone from GSK will correct me if I’m wrong). So you can see how the company might be wary of starting a big internal effort to explore a massive, complex, and risky new field of biology. Politically and psychologically, it’s probably easier for them to structure this in terms of an acquisition. (Source: In the Pipeline)

$720 million worth of sirtuin research

In the Pipeline — Thu, 24 Apr 2008 13:47:50 +0100

Well, I’m back from a brief vacation, and catching up with the news. It looks like the big headline is GlaxoSmithKline’s offer for Sirtris: $720 million, which is a hefty premium (84%!) to what the company was trading for previously. Reckless waste of money, or canny deal? I lean toward the latter, but I’ve long had a place in my heart for sirtuin research and its potential. It’s still a long shot, but it’s one of the most intriguing ones in the history of medicine. Actually, from one perspective, you wonder how long a shot it is: a biochemical pathway that seems to extend healthy life in yeast, roundworms, flies, and mice would seem to have some odds of doing the same thing in man. A lot of drug programs have been started with a lot less backing them up, albeit for rather less earth-shattering indications. Of course, Sirtris hasn’t officially been targeting life extension drugs, at least not in the near term. A number of these potential life-extending biochemical pathways are tied up with insulin signaling, which makes sirtuin-targeted drugs a natural for diabetic therapy as well. Sirtris has reported encouraging data for just that indication. If a sirtuin-based drug is going to make it to market, that’s a good bet for how it’ll do it. I note, though, that the company has also applied for orphan-drug status for resveratrol itself for a rare muscle disorder. But they don’t own that parent compound, just its use in this case – the diabetes work is being carried on with second- and third-generation analogs that address some of resveratrol’s problems. (It’s not a particularly stable compound, for one thing). Once one of these drugs is approved, it’ll have the biggest, strangest potential for off-label use that anyone has ever seen. Oh, that’s going to be something to watch. GSK is well aware of this – I’m not saying that it’s part of their business plan, but when you see their head of drug discovery talking to Forbes and tossing the word “transformational” around, you know that they’ve thought beyond a replacement for Avandia. The Wall Street Journal headlines it like it is: “Glaxo to Buy Sirtris in Bet on Antiaging Reseach”. That’s the truth, all right, and it’s going to be fascinating to watch things develop. As I was saying here the other day, a drug for aging is a perfect example of something the FDA has absolutely no idea of how to approach. Well, it’s not just the FDA, come to think of it: how on earth would you design a Phase II trial for life extension? How long would it take? What’s your clinical endpoint? And further on, how long will you want to monitor your Phase III patients (recall Pfizer’s recent follow-up of Exubera trial participants? How long will it take before you could be sure that some horrible bargain wasn’t struck along the way? That’s the lurking fear behind all this research, fit to give Leon Kass the shakes. Life extension tends to give some people the same “Things Man Was Not Meant to Know” shivers as (for example) germ-line genetic manipulation. I’m tempted to cue the theramin music in the background, but I can’t really make fun of this attitude, since I understand where the uneasiness is coming from. In all these cases, we’re looking at real alterations of what we think of as human. Personally, I think there’s room for improvement in what we think of as human, but I agree that we should reach for those improvements carefully. And I can see how the very thought could strike some people as coming close to crazy. But we’re going to find out. That’s the real import of the GSK news: the money is there to find out what’s possible in this field. I’m happy to hear it. But then, I was a bit euphoric back in 2003 when this news started breaking, and I’ve never really lost that feeling. We shall see. (Source: In the Pipeline)

Isotopic food (why was i not informed?)

Molecule of the Day — Thu, 24 Apr 2008 04:59:22 +0100

Is paying $5/liter for Fiji water not cutting it? Trying to come up with a more environmentally abhorrent, gauche hydration accessory? How would you feel about $1,000/liter, along with some iffy health benefits? Read the rest of this post... | Read the comments on this post... (Source: Molecule of the Day)

Why does cyanide pretend to be a weak field ligand in [cr(cn)5]3−?

Organometallic Current — Wed, 23 Apr 2008 13:23:00 +0100

Lord and Baik* Generally speaking, it is difficult to study Cr chemistry because many Cr complexes are paramagnetic. Computational modeling is also not easy due to spin contamination issues. This paper by Lord and Baik provides a rationale for the observation of (NEt4)3[Cr(CN)5] in a high-spin (S = 2) ground state, suggesting that one must consider both ligand−ligand electrostatic interactions and classical ligand−field arguments in order to have a full picture of spin-state energetic ordering in a transition metal complex. What they found here was that the Coulombic repulsion between the anionic cyanide ligands dominates the overall energetics of [Cr(CN)5]3−., making longer ligand−ligand separation more favorable and eventually leading to the high-spin complex. (Source: Organometallic Current)

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Big pharma’s big problem

The Chem Blog — Tue, 22 Apr 2008 19:03:22 +0100

A while back I was lucky enough to be accidentally selected to take a big shot from big pharma out to lunch while she was visiting. I say accidentally, because I’ve been a very vocal critic of big pharma’s business model, going so far as to actually do a seminar on the subject the first year I was in graduate school (kids, don’t do that.) My position isn’t that Big Pharma is evil and they’re out to get you, it’s that they’re big, stupid useless machines that pump out gobs of fluorinated shit for metabolic syndrome and boners and buy up little companies before their quarterly reports are up. None of them are hiring like they were a few years ago. Indeed, getting a job at these huge companies isn’t likely going to be the outcome for most people, regardless of the lab you work in. So, I took this lunch time opportunity to propose my own, rather arrogant opinion: It’s because they keep recruiting from Dave Evan’s lab. And Barry Trost’s lab. And Sam Danishefsky’s lab…. you know… as I so politely put it, the Legends of Total Synthesis. Of course, this doesn’t mean that all drug companies have stalled. Some how, we continue to get new drugs - they’re just not being made “in house” by big pharma. Look at my gheto-graph of New Drug Applications by year: If you’ll forgive the gayness of my chart, I pulled that data here, from the very government those drug companies have worked so hard to create for us. The blue line indicates the number of NDAs approved and, apparently, the only people that can really tell the difference between “the good years and the bad years” are John Lechleiter, Richard Clark, Jeff Kindler and/or any other douche bag that is lucky enough to be promoted to “transient CEO of big pharma for a few months.” An average of 90 ± 20. With a huge boom in the late 90’s where, I presume, most of those are still covered by the more realistic “25 year patents”. I remember back in 2002ish at Lilly when Big Syd Taurel got on the jumbotron in building 78 (there really is a huge screen and projector in the atrium - at least there was at the time) and announced that Lilly was going to enter into a hiring freeze because someone fucked up and lost the patent to Prozac before they could wring a few last good years out of it. Since then, it’s been a litany of unproven excuses like “It costs a BILLION dollars to discover a new drug and the Canadian reimportation/corporate taxes/generic competition/short patent/turrists/life is just draining all our money away and we’re operating on PENNIES, PENNIES I TELL YOU” and so on, yet - we can see from our friend the graph, that apparently some companies are doing just fine. But I was discussing the legends of total synthesis contribution to this. Pardon the digression. The problem, as I see it, is that people who work in these labs go on to fill the ranks of big pharma, who have done nothing, while little upstarts, which are filled with people from “lesser groups” at “lesser schools” appear to be doing alright. WTF gives? Is it… possibly… that total synthesis MAY NOT be the best training for drug discovery (heresy!). (Tip: the stock excuse is that you hear more from little companies because they’re more likely to announce their discoveries faster. Apparently, Big Pharma sits on ALL news, not just the bad news.) Or has Big Pharma academically inbred it self into Appalachian style banjo plucking retardation? It could be both, of course. I don’t think it’s just me, but it could be: does it seem like the groups with the largest anti-bio vibe are either material groups or total synthesis groups? While the obvious pitfalls of not appreciating the delicate biochemistry of the organisms you intend on eradicating may become apparent all too soon to the material folk, being anti-bio in a total synthesis lab is stupid, counter productive, and very prevalent. The new “multidisciplinary” action that compose 30% of Big Pharma powerpoint slides isn’t coming through in their hiring practices as they keep recruiting from labs that wouldn’t be able to find the active site of a protein if it were docked to the fatty part of their ass. It would be more logical to approach people who work in multidisciplinary labs, that make and model enzyme substrates - people who think like a biochemist but are trained as an organic chemist. The target in drug discovery is never known at the onset - if it were, the discovery process would be a lot easier. This is clearly not the case in total synthesis, where the target you’re synthesizing is known from day one and your mission is to make it, live or die trying. So I dropped these things on her and got back the stock responses which I’ve heard before (she is a proud alumni of the Evan’s lab, unsurprisingly)- “we need people who can think critically about chemistry.” To which I obviously replied, “I would think anyone obtaining a PhD in chemistry should have that ability.” Her answer was glib. “You’d like to think so…” suggesting, some how biochemists lack a certain part of their brain that performs these advanced critical thinking tasks and are awarded PhDs on the basis of “good, honest hard work if not pointless work.” Or, if I were to be even more cynical, that people who are in these legendary groups are always going to be critical thinkers and everyone else is too questionable to spend time interviewing. Which is bullshit, of course, but I’m just being cynical here. Obviously, if you want synthetic chemists, you’ll want to hire people with bench experience, but there’s no need to hire people from the same 10 or 15 groups. Apparently, anyone can use SciFinder now, so it’s largely unneeded to get people with broad encyclopedia knowledge of reactions and, at any rate, at some point companies need to look internally to determine why they are failing and, amongst other atrocious practices (including over use of direct-to-consumer marketing, out sourcing R&D and process to developing countries with governments that are blind to intellectual property theft, excessive executive compensation packages and top heavy managment structures… so on and so forth) they need to consider that they’re recruiting researchers poorly and their hiring strategy is pulling a homogenous pool of people and they’re doing it because 1. the people hiring were from those groups and 2. trying new shit is just not something huge, stupid drug companies do well or do quickly. I’ll end this rather long post with a cautionary disclaimer - I don’t do total synthesis but I’m also not interested in working for Big Pharma. I have no outward interest in these companies suddenly recruiting from… say… oh… some lab at Cal Tech. I also think TS is a great area to prepare chemists for work in drug companies - the issue is homogeneity and inbreeding, not that they’re failing to find quality people. ShareThis (Source: The Chem Blog)

Quick note

In the Pipeline — Mon, 21 Apr 2008 01:34:29 +0100

Just wanted to let everyone know that there probably won't be a post for Monday - I'm doing some traveling, and will have irregular access to the internet. No doubt huge stories will break during the day, while I'm unable to comment on them! At any rate, we'll see if I can get something up for Tuesday. See you then! (Source: In the Pipeline)

Druggies

The Chem Blog — Sun, 20 Apr 2008 20:34:51 +0100

So, out of about 375 of you (about 25% of Nature’s respondents) about 35% say that availability not being a factor you would essentially use some form of prescription drug to give yourself an intellectual boost, which is not too far above what Nature polled for people in the age group I assume my readership is in. I mean, possibly 10% higher, but these polls are horribly inaccurate anyway, so I’ll just call everything even and say, maybe if availability weren’t an issue, But it’s not as high as another number. Apparently, almost 60% of you have already tried a drug for recreational purposes already. Now… that’s interesting. I wouldn’t do it myself, actually, for a very singular and almost arbitrary reason: I can’t stand stimulants. I suppose Provagil isn’t really a stimulant, but I hate everything that prevents me from getting to sleep. I enjoy the taste of delicious warm coffee, so I do drink caffeine, but never after 4pm. I didn’t use the shit to stay awake as an undergrad and I don’t use it to stay awake now. Sleepiness is God’s gift to you. It means you’ve done a good day’s worth of work. Maybe that’s not a very good reason not to do it. I suppose there are no higher moral reasons in me that would keep me from taking any drugs to accomplish more in the lab, but let’s be frank, most of the problems I have with illegal drugs are non-existent: You’re using your own machinery. “Drugs” advance what you have - they don’t give you more. It’s not like they build gray matter, they just make it more avaliable These are high quality pharmaceuticals, not crack rocks. Quality wouldn’t be an issue Using FDA approved drugs does not perpetuate cross boarder illegal trade and perpetuate street violence I am not providing any more impetus to continue to fund the DEA than I absolutely need to There you have it. I don’t know if I can condone the use of drugs for performance enhancing purposes, but I don’t think I would mind if someone were using them. Unless someone can point out why I should care. ShareThis (Source: The Chem Blog)

Mercury beating heart

Molecule of the Day — Sun, 20 Apr 2008 20:22:05 +0100

Oscillating reactions are neat; I should write up one of my favorites sometime... Here, electrons flow from iron metal to mercury (I) sulfate to chromium (VI) oxide. Listen to the video for a step-by step explanation... Read the rest of this post... | Read the comments on this post... (Source: Molecule of the Day)

Molecules in the news...

Molecule of the Day — Sat, 19 Apr 2008 02:04:31 +0100

A couple previous molecules of the day were in the news today: polylactide and lead chromate. Read the rest of this post... | Read the comments on this post... (Source: Molecule of the Day)

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Cut it out. cut it out now.

In the Pipeline — Fri, 18 Apr 2008 12:11:24 +0100

File this under “does no one any good”. As many of you will have seen, JAMA just published a report on various studies that Merck has conducted and published over the years on Vioxx. The conclusion was that the company basically wrote the papers, and then went shopping for well-known academic names as authors. No, this one isn’t going to be good for anyone involved. There seems little doubt that this practice does go on. I’ve never been in a position to see it happen, but it’s been reported for years. There are whole companies whose business is “scientific writing and communication”, and some of these seem to be in the business of turning studies into manuscripts, with no mention of their work in the final version. (The JAMA article found evidence of this sort of thing as well). Scientific authorship is a messy business, true, and there are a lot of journal articles whose entire list of authors might have trouble with a pop quiz on the details of the paper. It is, in my mind, perfectly acceptable for one or two people on the author list to do most of the writing, with everyone else contributing suggestions and revisions. That’s how every paper I’ve been on (or written) has been done. But the worst of these Merck cases look like a search for a lead author or co-author, which is just unacceptable. At least one of the authors named in the article is disputing its conclusions. Stephen Ferris of NYU says that he was no figurehead, and calls the JAMA paper “egregious” for having done no follow-up with the people it names. I suspect that there will be others in his category – the JAMA offices are getting a lot of testy e-mails this week, I’m sure. Of course, even the guilty are going to be sending them, since no one wants acquiesce to the label of “paid shill for publication”. And that’s the problem. I can believe that the JAMA authors (Joseph Ross of Mt. Sinai et al.) could have cast their net too widely as they dug through the piles of discovery documents from the Vioxx litigation. But, unfortunately, I can’t believe that all their examples are mistaken. Enough chicanery goes on with authorship in purely academic settings – I can well believe that it happens in industry/academic collaborations. But that’s the problem right there: the idea behind such a collaboration is, at least partly, to lend credence to the study’s results. Rightly or wrongly, industry studies on marketed drugs are perceived as needing the help. It’s the money involved, of course. When an industrial group publishes a paper on cell physiology or on a new method for cleaning up palladium-catalyzed reactions, no one doubts the results. But when it’s something that might have a direct and immediate effect on millions of dollars in revenue, doubts naturally set in. They always will, even if the research is beyond reproach. And that’s why this ghostwriting business just makes the problem worse. I haven’t seen anyone suggesting that the Merck studies themselves are bogus – they had damn well better not be – but by playing games with the external author list, the company invites suspicion. I’m willing to bet that many people outside our industry who have just read the headlines on this story have assumed that the results were cooked up, just like the authorship. This is not what the industry needs. It never has been, and we need it less now than ever. If we’re going to win back the trust of the general public – which we’ve lost, in case anyone hasn’t noticed – we’re going to have to cut out the shortcuts, stop the doubletalk, and act as if what we’re doing (drug discovery) is something to be proud of. Sure, this is a business – we sell improved health for money, and since it sure costs money to do it, there’s nothing in that transaction to be ashamed about. So why are we acting as if the only way to do business is under the cover of darkness? We’re not going to have much of a business if these practices keep going on. Want price controls, real industrial-strength ones? Want lots and lots of marketing restrictions? Want the FDA to raise the bar for approval to levels never before seen? Want flocks of lawyers beating their wings, circling around our every move? Just keep it up, just keep this stuff up. We’ll get all that and more. (Source: In the Pipeline)

Getting smarter already?

In the Pipeline — Thu, 17 Apr 2008 12:28:45 +0100

There have been several articles in Nature recently about performance-enhancing drugs. But these aren’t steroids or blood-cell therapies: they’re performance enhancers for scientists and engineers. Chief among them are Ritalin (methylphenidate), Provigil (modafinil), and various beta-blockers, to enhance concentration and wakefulness. The whole topic came to the fore last December, in an article suggestively titled "Professor's Little Helper". Here are the results of their informal readership poll. It's not a huge trend, at least not yet. The fraction of their self-selected sample who had never taken any such compound was in the solid 70% range, and you'd expect people with some experience to be disproportionately represented in such a poll. But usage is out there, nonetheless. The first question to ask in these situations is, do such drugs work? As you’d guess, there’s no controlled data set to work with. There is, under current regulations, absolutely no way that any company with such a compound would run a trial for cognition enhancement in otherwise healthy people. The FDA has made it clear over the years that they are in the business of regulating drugs that help sick people, not ones for people who have no disease at all. In fact, I don’t think that the current regulatory framework even accommodates the idea of making people “better than well”, and if someone proposed such a study, it’s a solid bet that the FDA would turn it down. So, in the absence of anything rigorous, we have a flood of anecdotal data, which is what the Nature pieces are full of. Take that along with the many reports of students using these drugs, and you have something significant going on, which has been coming on for a while now. Back when I used to work on Alzheimer’s, we used to speculate about what would happen if we ever did come across something that usefully enhanced human memory. I was sure that a large off-label market would develop among college students. I have to admit, I never considered their professors. But do they work? Well, I’m willing to stipulate that they do, but I’m not sure to what extent. One confounding variable, which will be very hard to address outside of a controlled trial, is the placebo effect. I have to think that there’s a strong one in this area, that if you think you’ve taken something that helps your concentration and memory, that those functions will measurably improve. How much this counts for is impossible to say – but again, I’m willing to stipulate that there are pharmacological effects above and beyond placebo. In other words, I believe that a controlled trial of healthy individuals would, in fact, show improvement in cognition while taking such compounds. How much, and in what particular tasks, and for how long, and across what subgroups of people, and across what particular dosing regimens, and in what proportion to objectionable side effects, I have no idea. But I think that there’s something there. And there will be more. I feel sure that other compounds will be developed that affect normal cognition in what are (at least under some circumstances) are beneficial ways. They will not, however, be approved for that purpose. That’s a long, long way off. They’ll be approved for Alzheimer’s, or sleep disorders, or some category of attention deficit disorder, which is how we have the compounds we have now. This situation is similar to various possible anti-aging therapies. There, too, I think that compounds will come eventually that should be able to show benefits, according to what we understand about aging in other species. But they won’t be approved for that. They’ll be approved for diabetes, most likely, considering the strong links between insulin action and lifespan, or possibly for other slow-developing degenerative disorders. But if aging itself is a slowly developing degenerative disorder, what then? I’ve been meaning to write something about this story for a while, but one of the problems has been that I’m still quite divided about what I think about it. (Normally my opinions come to me more quickly, for better or worse). Some background: people who’ve known me personally for a while generally know that I’m personally very much opposed to chemically altering the way that I think or feel. I never drank in high school, for example, which I can tell you made me stick out a bit in late-1970s Arkansas. Nor did I in college or afterwards; I still don’t drink now. And that personal prohibition goes even more for other recreational drugs, as you’d imagine. My reason for that has long been that I enjoy my brain the way it is, and have seen no reason to mess up its function for fun. But the advent of cognition enhancing drugs is a scalpel to dissect that line of thought. What if the ingested chemicals add to some of the parts of my brain that I value the most? That “mess up its function” clause has been taken out and flipped upside down. And what if it’s for work, and not for recreation? Is that more allowable, because it’s somehow less frivolous? (All right then, what if I were to enjoy having a better memory, which I likely would?) That gets to a less creditable reason for my objection to alcohol and other such drugs – perhaps I’m not just objecting to them on practical grounds. Perhaps I’m objecting because I don’t want other people to have a good time, at least not like that. Food for, well, thought. I’m still working this one out, I have to say. The issue of caffeine will come up as I do – I don’t drink tea or coffee, actually, having never wanted to end up in the position of having to drink either to function. But I don’t object to caffeinated soft drinks, although I don’t generally seek them out. But I have, when I’ve needed to stay awake – so how high a horse can I get on, anyway? Caffeine is a good proving ground for positions on the newer compounds. Comments are, as always, welcome. I suspect that this is one of those issues that everyone has an opinion on. . . (Source: In the Pipeline)

Fun with bacteria

In the Pipeline — Wed, 16 Apr 2008 12:19:54 +0100

A recent interview in Nature Reviews Drug Discovery with John Powers, formerly of the FDA, points out some problems in designing antibacterial drug trials. Some of these are unique to this area, although others we're stuck with wherever we go. For one thing, it’s surprisingly hard to make sure, when you’re selecting patients, that the people you’re letting into the trial have the disease that you’re trying to treat. The example used is that some 5% of the patients who present with cough actually have pneumonia. Pneumonia is a very good disease to treat with antibacterial drugs, but you’d better make sure that your patients actually have it. There are some tests available to make sure that a given pathogen is present, although they aren’t available in every case you’d want them to be. If you don’t have such a screen, you risk having a very heterogeneous patient population, which will likely as not obscure the effectiveness of the drug you’re testing. Then there’s the related difficulty in treating some conditions that you’d think would be clear cases for antibacterials: ear infections, for example. The problem is, it’s surprisingly hard to show benefit for some of these things with existing drugs. The underlying infection may be hard to get to (poor circulation in the infected area), or it may be an intrinsically heterogeneous condition like sinusitis. (That can be the result of umpteen different sorts of bacteria, or it could well be something viral, or several varieties of fungal infection, or allergies, what have you). There’s no point in running a head-to-head with an existing medication in these cases; you should run against placebo. That'll be enough of a challenge. Another problem is that some of the bacterial diseases progress rather quickly – ahead, in some cases, of our ability to usefully diagnose them. That presents a real challenge for a clinical design, one that is dealt with, in many cases, by not attempting to gather rigorous clinical data under these conditions at all. In this field, diagnostic tools have to be fast if they’re going to be of much use. There are two sides to all these problems: not only do you want to get the drug to the people who need it (and who will respond to it) the most, you want avoid giving it to people who won’t respond at all. That’s not just for the reasons given above (it’ll mess up your data), although that’s enough all by itself. No, the other problem is that spreading your drug around to inappropriate patient populations will just bring on resistance even faster. That’s going to happen no matter what, of course – the key is to have it happen as slowly as possible. (Source: In the Pipeline)

Nickel-catalyzed decarbonylative addition of phthalimides to alkynes

Organometallic Current — Wed, 16 Apr 2008 10:49:00 +0100

Kajita, Matsubara,* and Kurahashi*This is an interesting reaction to make isoquinolones. Their design was quite logical and it did work at the first try, although the yield of the desired product was only 18%. The authors managed to improve the yield by the introduction of electron withdrawing Ar groups. The mechanism was proposed to proceed by a nucleophilic attack of Ni(0) to the amide moiety (an oxidative addition of C-N to Ni) followed by decarbonylation, insertion of the alkyne to the phenyl C-Ni bond, and finally reductive elimination of the product to regenerate the Ni(0) catalyst. The fate of CO was not mentioned, but I guess the bonded CO after the decarbonylation step was kicked out by the excess PMe3. (Source: Organometallic Current)

Phytic acid (think unositol? think again...)

Molecule of the Day — Wed, 16 Apr 2008 10:32:39 +0100

Phytic acid is an inositol derivative: Read the rest of this post... | Read the comments on this post... (Source: Molecule of the Day)

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Inositol (weird carbs)

Molecule of the Day — Wed, 16 Apr 2008 03:10:05 +0100

Inositol is a sugar: Read the rest of this post... | Read the comments on this post... (Source: Molecule of the Day)