Use of the nitrile oxide cycloaddition (NOC) reaction for molecular probe generation: a new class of enzyme selective histone deacetylase inhibitors (HDACIs) showing picomolar activity at HDAC6

  • J Med Chem. 2008 Aug 14;51(15):4370-3. doi: 10.1021/jm8002894.
Alan P Kozikowski  1 ,  Subhasish Tapadar ,  Doris N Luchini ,  Ki Hwan Kim ,  Daniel D Billadeau
Affiliations
  • 1. Department of Medicinal Chemistry & Pharmacognosy, Drug Discovery Program, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, USA. [email protected]
PMID: 18642892 DOI: 10.1021/jm8002894
Abstract

A series of hydroxamate based HDAC inhibitors containing a phenylisoxazole as the CAP group has been synthesized using nitrile oxide cycloaddition chemistry. An HDAC6 selective inhibitor having a potency of approximately 2 picomolar was identified. Some of the compounds were examined for their ability to block pancreatic Cancer cell growth and found to be about 10-fold more potent than SAHA. This research provides valuable, new molecular probes for use in exploring HDAC biology.

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