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Deuterating Chiral Centers Stabilizes Thalidomide Analogs

Method allows researchers to selectively deliver desired enantiomer

by Celia Henry Arnaud
March 16, 2015 | A version of this story appeared in Volume 93, Issue 11

CORRECTION: On April 6, 2015, this story was updated to correct the structure of the deuterated S enantiomer of CC-122.


Thalidomide, a racemic drug, is remembered for the birth defects it caused in the 1960s, but thalidomide analogs are now being developed and marketed as anti-inflammatory and anticancer agents. Typically, one enantiomer of a drug compound provides the therapeutic effect. The other enantiomer may be inactive or even detrimental to health. But delivering only the preferred enantiomer can be difficult when the enantiomers rapidly interconvert. By using a method called deuterium-enabled chiral switching, Sheila H. DeWitt of DeuteRx, in Andover, Mass., and coworkers stabilize the desired enantiomers of two thalidomide analogs, CC-11006 and CC-122 (Proc. Natl. Acad. Sci. USA 2015, DOI: 10.1073/pnas.1417832112). Deuterating the chiral centers significantly slows the racemization rate without affecting metabolism or pharmacokinetics of the compounds. The researchers find that in vitro anti-inflammatory and in vivo antitumorigenic properties of CC-122 are caused almost exclusively by the (–)-enantiomer, which is also more active than the racemic mixture. They have not yet determined the absolute configuration of the (–)-enantiomer but believe it is most likely the S form. The company plans to advance the compound as a drug for multiple myeloma, DeWitt says.


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