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Bioorg Med Chem. 2014 Jul 15;22(14):3720-31. doi: 10.1016/j.bmc.2014.05.001. Epub 2014 May 14.

Design and synthesis of novel and highly-active pan-histone deacetylase (pan-HDAC) inhibitors.

Author information

1
Nippon Pharmaceutical Chemicals Co., Ltd, 2-8-18 Chodo, Higashi-Osaka, Osaka 577-0056, Japan. Electronic address: t-tashima@nichiri.co.jp.
2
Nippon Pharmaceutical Chemicals Co., Ltd, 2-8-18 Chodo, Higashi-Osaka, Osaka 577-0056, Japan.

Abstract

Histone deacetylase (HDAC) inhibitions are known to elicit anticancer effects. We designed and synthesized several HDAC inhibitors. Among these compounds, compound 40 exhibited a more than 10-fold stronger inhibitory activity compared with that of suberoylanilide hydroxamic acid (SAHA) against each human HDAC isozyme in vitro (IC50 values of 40: HDAC1, 0.0038μM; HDAC2, 0.0082μM; HDAC3, 0.015μM; HDAC8, 0.0060μM; HDAC4, 0.058μM; HDAC9, 0.0052μM; HDAC6, 0.058μM). The dose of the administered HDAC inhibitors that contain hydroxamic acid as the zinc-binding group may be reduced by 40. Because the carbostyril subunit is a time-tested structural component of drugs and biologically active compounds, 40 most likely exhibits good absorption, distribution, metabolism, excretion, and toxicity (ADMET). Thus, compound 40 is expected to be a promising therapeutic agent or chemical tool for the investigation of life process.

KEYWORDS:

Cancer; Carbostyril; Epigenetics; Histone deacetylase; Histone deacetylase inhibitor

PMID:
24864038
DOI:
10.1016/j.bmc.2014.05.001
[Indexed for MEDLINE]

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