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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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June 3, 2008


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Posted by Derek

We recently encountered a problem that’s (unfortunately) a rather common one. An enzyme assay turned up an interesting hit compound, with some characteristics that we were hoping to see for leads against our target. A re-test showed that yes, the activity appeared to be real, which was interesting, since this hit was a welcome surprise from a class of compounds that we weren’t expecting much from.

It was a comparatively old compound in the files, and all we could find out was that it had been purchased rather than made in house. Looking around, it seemed that there were very few literature references to things of this type, and only one commercial source: the Sigma-Aldrich Library of Rare chemicals, known as SALOR. That, though, was a potential warning flag.

Those compounds come from an effort started by Aldrich’s Alfred Bader many years ago, who started trolling around various academic labs looking for unusual compounds that no one wanted to keep around any more. Over time the company has accumulated a horde of oddities that are often found nowhere else, but there are several catches. For one, these things are usually available only in small quantities, tens of milligrams for the most part. That’s plenty for the screening files, but you’re not going to make a bunch of analogs starting from what comes out of a SALOR vial. Another catch is that the compounds are sold, very explicitly, as is: the university sources tell Aldrich what’s on the label, so that’s what they sell you and caveat emptor all the way, dude.

So often as not, you get what we got, a nice-looking white powder which, on closer analysis, turned out to only have a vague relationship to the structure on its label. We knew that we were in trouble as soon as the first NMR came out: way too much stuff in one region, nowhere near enough in some others. Mass spec confirmed that this thing weighed more than twice as much as what it was supposed to. We’ve since pretty much nailed down what the stuff really is, and our interest in it has decreased as each of the veils has been removed from the real structure.

We’re correcting the data in our own screening files, of course. And yes, we’re going to tell the folks at Aldrich to change their label, too, assuming they have any of this stuff left. At least the next person will know what they’re getting. For once. But there are more of these things waiting out there – in every large compound collection, in every catalog, in every collection of data are mistakes. Watch for them.

Comments (4) + TrackBacks (0) | Category: Drug Assays | Life in the Drug Labs


1. petros on June 3, 2008 8:22 AM writes...


It can happend with inhouse stuff too, albeit I'd guess less frequently now.

In the WDF a certian "tricylcic" showed up as a great hit but when more was required it proved impossible to make. But testing showed that the final step had never resulted in cyclization- someone either didn't run or had ignored the NMR!

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2. SP on June 3, 2008 8:41 AM writes...

We're changing out collection so that we only screen things that are >75% pure by in-house LCMS- anything else is purged from the screening deck. No more mystery mixes.

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3. Chris C on June 3, 2008 9:50 AM writes...

As a molecular biologist I can tell you that we are not immune to this problem. I cannot tell you how many plasmids, strains, and cell lines turn out not to be what I expected. I haven't had this problem in a commerically purchased product, which is probably the best reason to purchase a plasmid from a company rather than getting it from somebody. From now on I will sequence important parts of all my new plasmids and at the very least do a restriction digest. Laziness about these precautions is one of the leading causes of wasted time.

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4. Merkwurdigliebe on June 3, 2008 10:29 AM writes...

Caveat Emptor, indeed. Adding a compound to the library without verifying it's identity is rather like buying a house site-unseen.

I wonder where Aldrich found it.

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