Macrolactams bind to heat shock protein 90

Posted on behalf of Steve Moore, web writer for Organic & Biomolecular Chemistry

The heat shock protein 90 (Hsp90) has a key role in some oncogenic pathways and is a widely studied target for anti-cancer therapeutics. The search for small molecule inhibitors of Hsp90 is ongoing. The most potent in vitro inhibitor of Hsp90 is radicicol, a resorcylic acid lactone; however radicicol lacks activity in vivo, possibly because of the presence of readily metabolised functional groups.

In their search for new inhibitors of Hsp90, scientists from the University of Nottingham and the University of Sussex have synthesised a series of macrolactam radicicol analogues. A new synthetic route to N-methylated resorcylic acid macrolactams is described which permits convenient variation of ring size. Macrolactam binding to Hsp90 was demonstrated by isothermal calorimetry and conformational changes were observed in co-crystallization experiments with yeast Hsp90.

Synthesis of macrolactam analogues of radicicol and their binding to heat shock protein Hsp90
Bridie L. Dutton, Russell R. A. Kitson, Sarah Parry-Morris, S. Mark Roe, Chrisostomos Prodromou and Christopher J. Moody
Org. Biomol. Chem., 2014, DOI: 10.1039/C3OB42211A, Paper

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