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May 14, 2012
Bosutinib: Don't Believe the Label!
Now here's a worrisome thought, if you're doing kinase research. A tyrosine kinase inhibitor in the clinic against Bcr-Abl, bosutinib (SKI-606), is also being used as a research tool in a number of academic groups. But they're probably not using what they think they're using.
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?
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