The researchers (from Princeton) looked at the effects of the antidepressant sertraline, a serotonin reuptake inhibitor. They did a careful study in yeast cells on its effects, and that may have some of you raising your eyebrows already. That's because yeast doesn't even have a serotonin transporter. In a perfect pharmacological world, sertraline would do nothing at all in this system.

We don't live in that world. The group found that the drug does enter yeast cells, mostly by diffusion, with a bit of acceleration due to proton motive force and some reverse transport by efflux pumps. (This is worth considering in light of those discussions we were having here the other day about transport into cells). At equilibrium, most (85 to 90%) of the sertaline that makes it into a yeast cell is stuck to various membranes, mostly ones involved in vesicle formation, either through electrostatic forces or buried in the lipid bilayer. It's not setting off any receptors - there aren't any - so what happens when it's just hanging around in there?

More than you'd think, apparently. There's enough drug in there to make some of the membranes curve abnormally, which triggers a local autophagic response. (The paper has electron micrographs of funny-looking Golgi membranes and other organelles). This apparently accounts for the odd fact, noticed several years ago, that some serotonin reuptake inhibitors have antifungal activity. This probably applies to the whole class of cationic amphiphilic/amphipathic drug structures.

The big question is what happens in mammalian cells at normal doses of such compounds. These may well not be enough to cause membrane trouble, but there's already evidence to the contrary. A second big question is: does this effect account for some of the actual neurological effects of these drugs? And a third one is, how many other compounds are doing something similar? The more you look, the more you find. . .

And it's not like plain phenol itself has no odor. It's strong, penetrating, and completely unmistakable. As soon as I get a whiff of the stuff, I'm immediately transported back to the Verser Clinic, the small hospital in the town I grew up in back in Arkansas. Phenol smells like an old-fashioned medical office; it was used for many years as a disinfectant (and was, in fact, introduced as such by Joseph Lister himself). If you move it down a notch to sulfur, you get thiophenol, which is easy to describe: burning rubber - the pure, potent, platonic ideal of burning rubber, bottled up and daring you to open the cap. I can't say that I won't work with thiophenol, since I have (very much to my regret, at times), but I've used it most reluctantly, and probably haven't touched it in at least fifteen years.

Ah, but move down one more element and you have selenophenol, and that's a more exotic reagent. I've never seen any, and after reading the descriptions, I never want to. Actually, let me take that back: I'd look at some from the other end of the lab. What I never want to do is open any of it up. The chemical literature has numerous examples of people who are at a loss for words when it comes to describing its smell, but their attempts are eloquent all the same. A few years ago, Gaussling at the Lamentations on Chemistry blog referred to it as "The biggest stinker I have run across. . .Imagine 6 skunks wrapped in rubber innertubes and the whole thing is set ablaze. That might approach the metaphysical stench of this material." So we'll start with that.

I believe that this lovely compound is commercially available (if you're anywhere close to anyone making it, you'll know about it). But should you wish to prepare it with your own hands, do violence to your own schnozz, and drape yourself out of your own window while you throw up into your own rhododendrons, feel free to use this reliable preparation from Organic Syntheses, circa 1944. This features the note that "it is frequently advisable to work with [selenium compounds] on alternate days", which I suppose is to give them time to work their way out of your nasal passages.

I'm not so sure. When I was a teaching assistant in grad school, I taught three labs a week one semester, and one of those labs, damn it all, was the phenyl Grignard reagent. We had them making it in diethyl ether, outside of the small and inadequate fume hoods, and the solvent fumes were fit to strip paint. By the end of the Monday lab, I was well saturated with ether and had a terrible headache, which returned as soon as I caught my first whiff of the stuff on Tuesday afternoon. I barely made it through that lab, mostly by holding my breath and using a lot of hand gestures, and I took the opportunity on Wednesday to get as much fresh air as I could. But when I came back for the Thursday session, the first first wave of ether vapor washed over me and nearly stretched me out on the tiles. I taught the entire lab from the hallway, shouting and waving like Monty Python's "Semaphore Version of Wuthering Heights". So in my mind, the choice between getting these things over with and stretching them out is still not settled.

That Org Syn prep also notes that it can produce small amounts of hydrogen selenide, which is very toxic indeed (and will give you a sore throat, too, apparently, before it kills you). This luckless graduate student from the 1920s got to experience both of these bracing selenium room fresheners in the course of his work:

Berzelius described the poisonous effect of hydrogen selenide quite impressively; "In order ta get acquainted with the smell of this gas I allowed a bubble not larger than a pea to pass into my nostril ; in consequence of its smell I so completely loss my sense of smell for several hours that I could not distinguish the odor of strong ammonia even when held under my nose. My sense of smell returned after five or six hours, but severe irritation of the mucous membrane set in and persisted for a fortnight' The writer has been working on the gas for some time and was also quite seriously affected once, the injury persisting for many days. That it is more poisonous than the hydrogen sulphide is well known."

So you have that to look forward to on your way to selenophenol. And at your destination? Assuming your nose is still attached to your face, you'll experience what few chemists ever have. I'll let this 1908 report from Wisconsin take over:

When benzeneselenonic acid in solution is treated with reducing agents such as hydrogen sulphide, sulphur dioxide, or, best, with zinc and hydrochloric, acid selenophenol is obtained as a yellow oil with an overpowering and most nauseating odor. . .The odor of diphenyl diselenide is extremely disagreeable but is not nearly so bad as that of selenophenol.

. . .The effect of selenophenol on the skin is very similar to that of thiophenol, forming blisters which itch intensely. After a time, these dry up, the skin scales off, and there appears to be a deposit of red selenium beneath it. The odor of selenophenol is very penetrating, and is nauseating beyond description.

Gloves, man, gloves. Unless, of course, you wish to be tattooed with elemental selenium while being nauseated beyond description. Should this be your idea of a fun Saturday night, I will not stand in your way.

This article has the details. The compound has a dichloromethoxy aryl group hanging off of it, and apparently someone has been making (or made one good-sized batch of) the wrong isomer. Instead of 2, 4-dichloro-5-methoxy, many commercial samples appear to be 3,5-dichloro-4-methoxy. This got noticed at first by inspection of an X-ray structure deposited in the Protein Data Bank, 3ZZ2, from a group at Oxford. A postdoc at Stanford saw that something was off, and at the same time, he was having trouble matching his own X-ray data with the known structure of the compound.

The explanation wasn't what anyone wanted to hear, for sure. The two groups had purchased their material years apart, from different vendors. The count of vendors selling the wrong material is now up to thirteen and climbing. That link also suggests a possible earlier source of the problem: some of the commercial supplies of 2,4-dichloro-5-methoxy aniline are not the right material. Whoever made this bosutinib may well have thought that they were right on target.

Odds are, some batch of the wrong stuff has been resold through the supplier community since at least 2006 - this sort of thing goes on all the time. But the tricky part here is that LC/MS wouldn't have told you that there was a problem, unless you had an authentic sample to check the retention times (which would have been pretty darn close, anyway, I'd guess). The mass is, of course, the same. And the NMRs of the authentic and mis-labeled stuff would be different, but not on casual inspection, for sure (same number of aryl protons). No, I would have let this stuff through, I've no doubt about that. Makes a person wonder what else on the shelf is the wrong material, doesn't it?

". . .as a member of a growing biopharma company I am tasked with evaluating the effectiveness of industrial post-docs from both a business perspective and the post-doc's experience. Specifically, we are considering adding one for a short-term (2yr) to add headcount to a project. This adds resources without the long term commitment and also gives the scientists on site a chance for a paper they otherwise might not have time to work on. The candidate obviously gets a well-paid post-doc experience, and an industrial foot in the door. But, does this model work? I imagine that if it were that cut and dried you would see more of them."

Good point. Industrial post-docs are still relatively rare, although I've certainly seen a few. Come to think of it, though, those were mostly in biology, as opposed to chemistry. So, what do people think? From my end, I'd say that traditionally, companies have felt that temporary positions are best filled with experienced temporary employees, who presumably don't have to be trained as much. And if you're going to hire someone to learn the ropes, they might as well be good enough to be brought in as a full-time employee.

From the other end, an industrial post-doc has always been seen as less prestigious than an academic one, and there are some hiring managers who probably don't know what to think when one shows up on a c.v. There's often a feeling that if the person did a really good job during the post-doc that the company would have tried to offer them something permanent. And since they didn't, well. . .

Even so, it does seem as if there are situations where an industrial post-doc could be a good fit, and in today's job market, anything looks good. Anyone out there experienced this, from either end?

But there's more. Meetings are a big source of disclosure, as witness the Wall Street frenzies around ASCO and the like. Talks and posters release information that won't show up in the literature for a long time (if indeed it ever does). And there are plenty of other avenues. The question is, though, how much time and money do you want to spend on this sort of thing?

There are commercial services (such as Integrity) that monitor companies, compounds, and therapeutic areas in this fashion, and they're happy to sell you their services, which are not cheap. But figuring out the cost/benefit ratio isn't easy. My guess is that these things, while useful, can be thought of as insurance. You're paying to make sure that something big doesn't happen that you're unware or (or unaware of in enough time).

So here's a question for the readership: has competitive intelligence ever made a big difference for you? Positive and negative results both welcome; "I'm so glad we found out about X" versus "I really wish we'd known about Y". Any thoughts?

Along the way, one learns that the discoverer of palladium (Wollaston) could never interest anyone in the metal, and almost all of it that he'd extracted was still sitting on the shelf, unsold, at his death. Time vindicated him, and how - it's now perhaps the most essential catalytic metal in the world. The late 1960s were a turning point:

Entry of Richard Heck: Following post-doctoral studies, Heck accepted a position at Hercules Powder Co where he was afforded freedom that is seldom experienced by the modern industrial chemist. Briefed with the task of “doing something with transition metals,” Heck investigated the chemistry of cobalt carbonyl complexes. Although this work generated many interesting observations, finding profitable applications for his research proved difficult. Inspired by his colleague Pat Henry's work on the Wacker oxidation, Heck's attention turned in the direction of arylpalladium chemistry.

He tried Wacker-type conditions with other reagents around to try to intercept the palladium intermediate, and organomercurys obliged with an immediate reaction. The story from there is a trip through a good swath of the periodic table, and the development of an awful lot of knowledge and expertise in metal complexes. Enter then Mizoroki, Kumada, Sonogashira, Negishi, Stille, Suzuki and many others. It's a long, complex, story, but this paper should serve as the definitive overview, and an excellent look at how chemistry (and science in general) go about discovering and developing things.

A statement from Wiley said that "Publishers enable content digitisation, rigorous peer review, strong editorial infrastructure and support and investment in an effective online platform for dissemination." And yes, they do those things. But how well do they do them? And how well do they do them for the prices they charge? I'm glad that these arguments are finally out on the table.

An erratum with the right figures 3 and 4 will be published soon in Biomaterials. The right lifespan values after the beginning of the treatment are given in the original text without any change. To sum it up, the extensions of lifespans are twenty months and sixteen months with respect to water-treated controls and olive-oil-treated controls, respectively.

Our original objective was not to study lifespan extension but the toxic effects of C60 at reiterated doses. Lifespan extension by C60 is not really surprising, all the more so as it had already been shown by others that some C60-derivatives can prolong lifespans in several experimental models, albeit moderately.

What is really surprising in our results is that C60 acts at very low doses, which means that the effect is very strong, and that this effect lasts for a long time after the end of the administration. A possible explanation is that some C60 precipitated inside the reticulo-endothelial system and then slowly dissolves and diffuses.

Of course we understand that non C60 specialist readers are incredulous about these results, as it could be expected.

We hope now that others will try and confirm our results. If our results are confirmed by others, which we firmly believe, it will be then necessary to try to reproduce these experiments on bigger samples including other species and of course to optimize the dose and the duration of the treatment.

I share that hope that others will try to confirm the results. It'll be a while, most likely, before we hear about anything in this area, but when something comes up, I'll blog about it.

Well, prepare yourselves for another technology for exploring the wild blue yonder. A new paper in Angewandte Chemie from a group at the CEA (Gif sur Yvette, France) outlines an immunological detection scheme. They have antibodies to an imidazole derivative, and antibodies to a phenolic moeity as well. So both structures are attached to a range of functional groups and combined with heat and/or metal catalysts to see if anything happens. A sandwich assay at the end with the different antibodies gives you a yellow color only if a compound has been formed that has both ends present; that is, if a coupling reaction of some sort has occurred.

They ran 3360 reactions, each on a 100 nmol scale (there's the sensitivity of the antibodies for you). Two new reactions were discovered - an isourea synthesis (which can lead to benzoxazoles) and an alkyne reaction leading to thiazole derivatives. Neither of those is going to set the world of organic chemistry ablaze, but as a proof of concept, I'm convinced that this technique can work. So what do you do with it next?

One plan looks to be discovering new bioorthogonal reactions, couplings that can take place either inside or on the surface of living cells. The immunological detection is so sensitive that products can be teased out of all sorts of messy mixtures, apparently even cell lysates. I'd also encourage them to try some other conditions, such as various photochemical setups, to see what might be out there - it's a much less explored field than copper-catalyzed coupling reactions.

Like it or not, I think we're going to be seeing more of this sort of work. We might as well make the most of it!

So it can't be said that this is a widespread phenomenon. One would also want to see the numbers broken down by age cohort, and (especially) by field of study. The examples in the article are all history and English types. Also, if those figures are correct, the headline could have just as easily read "Master's Degree Holders Ten Times More Likely To Be On Food Stamps".

Honestly, the number I find most alarming in that chart is the total number of advanced degree holders. We went from 20 million in 2007 to 22 million in 2010 - two million more in only three years? The population of the country went from 301 million to 313 million during that time, so that's a pretty good crop of degree holders. Given what the economy has been like during that period, I'm surprised the food stamp figures aren't even higher.

Looking at advanced degrees as a percentage of the population, we have 4.3% in 1970, 7.2% in 1980, 8.8% in 1990, 8.6% in 2000 (a decrease I'm at a loss to explain), and 10.6% in 2009. Those figures don't quite add up with the ones in the food stamp article, but the trend certainly is in the same direction. We have figures in the growth in bachelor's degree or higher going back to 1940, and they show the relentless uptrend you'd expect.

So it shouldn't come as a surprise that well-educated people are participating more in some of the downsides that hit the rest of the population. Well-educated people are becoming more and more of the population.

Of course, you are right: in the published figure 4 the GAog and GAip panels are identical. These two panels were meant to represent the well-known effect of intra-peritoneally (i.p.) administered CCl4 on rat livers. The mistake was obviously due to the fact that the pretreatment of control animals with water either orally (GAog) or i.p. (GAip) cannot influence the effects of CCl4 on livers. Therefore the effects on liver are identical and the corresponding figures are expected to be closely alike. Anyway we sent to the Editor an erratum that will be published soon.

We are very grateful to you for warning us about this figure. We are very furious against ourselves. We still do not understand how such error could have escaped our notice during the revision process. While this mistake has not any influence on the validity of the results described in the text, this could raise a certain amount of doubt over the work. The extension of the lifespan of rats is real and we fear that our error could delay or even prevent control experiments we are expecting to be made by others.

We have published on C60 toxicity since 1995 and all our results have been confirmed by several independent teams. . .

That point in the second paragraph is an important one: if these results are real, they're quite important and interesting. But, as with any other scientific result, they won't be accepted as real until they've been replicated, and replicating this experiment is already a substantial undertaking. The mistake with the figures doesn't help to get these started. (I should note that I've also called the authors' attention to the other points raised here in the comments).

My hope is that other groups studying longevity effects in rodents (and having already made the commitment that entails) will be able to add a C60 arm to their experiments as a comparison.