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Biological Chemistry

Reactions May Help Drugmakers Add ‘Magic Methyls’ More Easily

Complementary techniques enhance molecules with methyl groups to aid the search for bioactivity-enhancing sweet spots

by Carmen Drahl
April 14, 2014 | APPEARED IN VOLUME 92, ISSUE 15

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Medicinal chemists invoke the “magic methyl effect” whenever they find that adding a single methyl group profoundly improves a molecule’s biological effectiveness—sometimes by as much as 100-fold. Researchers want late-stage techniques for attaching methyl groups so they don’t have to start syntheses from scratch. Now, two complementary reports offer that possibility. Reasoning that methylated products would be difficult to separate from similar-looking starting materials, Phil S. Baran of Scripps Research Institute, La Jolla, Calif., and colleagues installed a masked methyl group on myriad biologically active heterocycles and then unmasked the methyl (J. Am. Chem. Soc. 2014, DOI: 10.1021/ja5007838). To carry out their chemistry, they invented zinc ­bis(phenylsul­fonylmethanesulfinate) (PSMS), which behaves as an electrophilic radical and is inspired by a naturally occurring methylating agent, S-adenosyl­methionine. Meanwhile, Daniel A. DiRocco and colleagues at Merck Research Laboratories used an iridium catalyst to add methyl, ethyl, and cyclopropyl groups to heterocycles with photoredox catalysis (Angew. Chem. Int. Ed. 2014, DOI: 10.1002/anie201402023). They modified drugs including Claritin (loratadine) and Chantix (varenicline). The Merck process involved purifications with preparative-scale HPLC, but it worked on pyridines that currently perform sluggishly with the Scripps chemistry.

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