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Novel inhibitors of human histone deacetylases: design, synthesis, enzyme inhibition, and cancer cell growth inhibition of SAHA-based non-hydroxamates.

Abstract：

:To find novel non-hydroxamate histone deacetylase (HDAC) inhibitors, a series of compounds modeled after suberoylanilide hydroxamic acid (SAHA) was designed and synthesized. In this series, compound 7, in which the hydroxamic acid of SAHA is replaced by a thiol, was found to be as potent as SAHA, and optimization of this series led to the identification of HDAC inhibitors more potent than SAHA. In cancer cell growth inhibition assay, S-isobutyryl derivative 51 showed strong activity, and its potency was comparable to that of SAHA. The cancer cell growth inhibitory activity was verified to be the result of histone hyperacetylation and subsequent induction of p21(WAF1/CIP1) by Western blot analysis. Kinetical enzyme assay and molecular modeling suggest the thiol formed by enzymatic hydrolysis within the cell interacts with the zinc ion in the active site of HDACs.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Suzuki T,Nagano Y,Kouketsu A,Matsuura A,Maruyama S,Kurotaki M,Nakagawa H,Miyata N

doi

10.1021/jm049207j

keywords:

subject

Has Abstract

pub_date

2005-02-24 00:00:00

pages

1019-32

issue

4

eissn

0022-2623

issn

1520-4804

journal_volume

48

pub_type

杂志文章

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