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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: derekb.lowe@gmail.com Twitter: Dereklowe

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« Drug Discovery on Radio 4 | Main | Publishing Without Consent »

May 23, 2012

How Come?

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Posted by Derek

I'm baffled by this abstract. Why would you go to the trouble of putting an unusual group (a ferrocene) on a molecule, and then show that putting it on seems to do little or nothing to the properties and activity of the parent compound? "We put a ferrocene on and it didn't kill the molecule" doesn't seem to be enough grounds for a full J. Med. Chem. paper. Does it?

Comments (21) + TrackBacks (0) | Category: The Scientific Literature


COMMENTS

1. Aaronap on May 23, 2012 11:34 AM writes...

Completely agree. Perhaps they were looking for a big, bulky lipophilic group to replace the phenyl ring, but I can think of a lot of other groups I'd put on before a ferrocene. I think this falls into the category of "we could do it, so we did it." Especially enjoyed the last sentence of the abstract--ferrocenes aren't predicted well because no one ever bothered to include them in the training sets!

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2. darwin on May 23, 2012 11:53 AM writes...

Pharmacokinetics or strategic cell target partitioning, perhaps?

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3. Curt F. on May 23, 2012 12:21 PM writes...

I haven't read the paper, but...maybe the ferrocenyl molecule makes for easier analysis. The iron might make solving crystal structures easier. I don't know NMR or IR very well but maybe the ferrocenyl gives a signal that is easy to detect. Maybe you could even do in vivo imaging?

Anyway, I don't read J. Med. Chem. enough to know if the paper belonged in that particular journal, but I'm curious if the readers of J. Med. Chem. who find this contribution unfitting can think of another journal that would make sense for this research.

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4. partial agonist on May 23, 2012 12:51 PM writes...

Maybe you can purify it using magnets, simplifying the workup!

What is really does is bust a patent, I suppose. Don't know if they have filed one.

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5. DCRogers on May 23, 2012 12:52 PM writes...

As I would have expected it to kill activity, it being well-tolerated is worthy of note. Or, perhaps, *as* a note, rather than a paper?

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6. agsone on May 23, 2012 12:54 PM writes...

I think it's more a case of bad choice of structures in the abstract rather than a bad paper. Looking at Table 1 in the paper it looks like the phenyl derivative has fairly flat SAR against the carbonic anhydrase isoforms while various ferrocenyl derivatives have (ca. 10-fold) increases in activity against specific isoforms. Should make them useful "tool compounds" if nothing else.

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7. MoMo on May 23, 2012 1:00 PM writes...

Why not put on a turgid Ferrocene? Its a cyclindrical aromatic group and the only one of its kind and phallic in nature, without being perverse.

Innovations from Australia and Italy at the same time! Amazing!

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8. HBF on May 23, 2012 1:35 PM writes...

What about using some radioactive isotope of iron in the ferrocene and then you could just watch where the thing goes. If you could do this with other molecules (attach a ferrocenyl group and not alter the activity) it'd be an easy way of tracking the concentration of a molecule inside the body or whatever you like!

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9. Chris D on May 23, 2012 1:44 PM writes...

There is the persistent complain/concern that negative results don't get published and published results skew toward the startling and unreproducible. Can we have it both ways?

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10. Pete on May 23, 2012 1:49 PM writes...

Nice try, partial agonist (#4), but the electrons of ferrocene are boringly (Bohringly?) paired making it diamagnetic. Maybe the drug of choice for anaemic sufferers of glaucoma?

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11. Buy and Bye on May 23, 2012 2:45 PM writes...

Makes you wonder if the nature of the chemistry pointed the manuscript to unbiased (eg, not organometallic chemist) reviewers. I do agree: we absolutely benefit by seeing the negative results of well thought out ideas/experiments, but... if that ends in "we stuck this bicycle tire on the active core and it didn't work" you must be disappointed.

Is there something clever about ferocenes and carbonic anhydrase?

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12. Kugelrohr on May 23, 2012 5:12 PM writes...

Nothing wrong with this paper. Looks like a nice piece of unusual SAR - why criticizing it?

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13. Narcissus on May 23, 2012 9:52 PM writes...

"Mirror, mirror on the wall, who has the most papers of all?"

"Why it's you Claudia!"

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14. Morten G on May 24, 2012 3:13 AM writes...

Really? You disliked this paper?
They did Caco-2 permeability tests and liver microsomes. They had a negative control where they stuck a gluco-thingie off instead which also behaved as expected in the assays. I can find no fault. With them at least. Don't be a dick, Derek.

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15. ddd on May 24, 2012 3:14 AM writes...

There is a precedent for ferrocene attachment to generate reactive oxygen species (ROS) in situ (see ferrocifen and many others).

This is just like that but without the ROS bit.

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16. John Wayne on May 24, 2012 6:58 AM writes...

I agree with some of the other commenters in that data like this is interesting enough to publish. I agree with Derek and take issue with where it was sent. J Med Chem is the premier journal for medicinal chemistry; this interesting but currently 'not that interesting' bit of data belongs in ACS Med Chem Lett at best, and probably in BMCL.

Summary: this belongs out there, but not in the front of the line; I don't send my average work to J Med Chem and neither should you (caveat: I'm an industry guy and am not disproportionately rewarded for shooting high in journals).

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17. Orthogon on May 24, 2012 7:53 AM writes...

We used to joke in grad school that the next paper that would come out of the lab in question would be, "Novel Ham Sandwich-Based Sulfonamides are Selective Inhibitors of One of the Fifteen Carbonic Anhydrases." Iron sandwiched between two Cp molecules isn't too far off.

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18. Hap on May 24, 2012 9:02 AM writes...

9: Negative results need to be published, but I don't see the point in publishing not-so-exciting results in JACS - they need to go somewhere appropriate to the importance and interest of the result (which is subjective, but still). The proliferation of journals means that there's always somewhere else to put a paper. Maybe Bioorganic and Medicinal Chemistry or European Journal of Medicinal Chemistry would have been better places to have published this.

It doesn't look very exciting to me, because it's not all that hard to get benzenesulfonamide carbonic anhydrase inhibitors with reasonably low Ki values (1-100 nM). The lipophilicities and permeabilities may be harder to tune (that might be why the commercial ones are at the upper end of the above range and aren't benzenesulfonamides), but I don't know. I assume I'm missing the novelty?

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19. Iridium on May 25, 2012 1:51 AM writes...

I think is rather interesting to have permeability data and methabolic stability info on unusual chemistry structures.

We might learn something new about the system we are working on.

People focus way too much on Ki.
Title might have been a little different to point that out.

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20. MoMo on May 25, 2012 7:16 PM writes...

Ferrocene has been around since Woodward.

Nothing new.....Except Derek being a "dick".

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21. dvizard on May 28, 2012 7:10 AM writes...

The Supuran lab is basically a factory for mass production of CA inhibitors. Plus he obviously must know some people in lead of the JMC; he's got a fuckton of papers out there, all of them similarily relevant to me...

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