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J Med Chem. 2007 Nov 1;50(22):5425-38. Epub 2007 Oct 11.

Design, synthesis, structure--selectivity relationship, and effect on human cancer cells of a novel series of histone deacetylase 6-selective inhibitors.

Author information

1
Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603, Japan.

Abstract

To uncover novel histone deacetylase 6 (HDAC6)-selective inhibitors and to elucidate the structural requirements for their inhibitory activity, we designed and prepared a series of thiolate analogues based on the structure of an HDAC6-selective substrate and evaluated their properties by Western blotting and enzyme assays. Several thiolate analogues were found to be potent and selective HDAC6 inhibitors. Study of the structure-selectivity relationship revealed that the presence of a bulky alkyl group and tert-butylcarbamate group in these compounds is important for HDAC6-selective inhibition. Compounds 16b and 20b, the most selective and active compounds in this series, exerted a synergistic inhibition of cancer cell growth in combination with paclitaxel. They also blocked the growth of estrogen receptor alpha-positive breast cancer MCF-7 cells that had been treated with estrogen. These findings suggested that HDAC6-selective inhibitors have potential as anticancer agents.

PMID:
17929798
DOI:
10.1021/jm7009217
[Indexed for MEDLINE]

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