Design, synthesis, and evaluation of cyclic amide/imide-bearing hydroxamic acid derivatives as class-selective histone deacetylase (HDAC) inhibitors

Chihiro Shinji, Satoko Maeda, Keisuke Imai, Minoru Yoshida, Yuichi Hashimoto, Hiroyuki Miyachi

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49 Citations (Scopus)

Abstract

A series of hydroxamic acid derivatives bearing a cyclic amide/imide group as a linker and/or cap structure, prepared during our structural development studies based on thalidomide, showed class-selective potent histone deacetylase (HDAC)-inhibitory activity. Structure-activity relationship studies indicated that the steric character of the substituent introduced at the cyclic amide/imide nitrogen atom, the presence of the amide/imide carbonyl group, the hydroxamic acid structure, the shape of the linking group, and the distance between the zinc-binding hydroxamic acid group and the cap structure are all important for HDAC-inhibitory activity and class selectivity. A representative compound (30w) showed potent p21 promoter activity, comparable with that of trichostatin A (TSA), and its cytostatic activity against cells of the human prostate cell line LNCaP was more potent than that of the well-known HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA).

Original languageEnglish
Pages (from-to)7625-7651
Number of pages27
JournalBioorganic and Medicinal Chemistry
Volume14
Issue number22
DOIs
Publication statusPublished - Nov 15 2006

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Keywords

  • Class selectivity
  • Cyclic amide
  • HDAC
  • HDAC inhibitor
  • Hydroxamic acid

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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