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

Research output: Contribution to journalArticle

47 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
Externally publishedYes

Fingerprint

Bearings (structural)
Imides
Hydroxamic Acids
Histone Deacetylase Inhibitors
Amides
Histone Deacetylases
Derivatives
trichostatin A
Cells
Thalidomide
Cytostatic Agents
Structure-Activity Relationship
Zinc
Prostate
Nitrogen
Cell Line
Atoms

Keywords

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

ASJC Scopus subject areas

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

Cite this

Design, synthesis, and evaluation of cyclic amide/imide-bearing hydroxamic acid derivatives as class-selective histone deacetylase (HDAC) inhibitors. / Shinji, Chihiro; Maeda, Satoko; Imai, Keisuke; Yoshida, Minoru; Hashimoto, Yuichi; Miyachi, Hiroyuki.

In: Bioorganic and Medicinal Chemistry, Vol. 14, No. 22, 15.11.2006, p. 7625-7651.

Research output: Contribution to journalArticle

Shinji, Chihiro ; Maeda, Satoko ; Imai, Keisuke ; Yoshida, Minoru ; Hashimoto, Yuichi ; Miyachi, Hiroyuki. / Design, synthesis, and evaluation of cyclic amide/imide-bearing hydroxamic acid derivatives as class-selective histone deacetylase (HDAC) inhibitors. In: Bioorganic and Medicinal Chemistry. 2006 ; Vol. 14, No. 22. pp. 7625-7651.
@article{41f2c0f8409340eba54d1698723d76d6,
title = "Design, synthesis, and evaluation of cyclic amide/imide-bearing hydroxamic acid derivatives as class-selective histone deacetylase (HDAC) inhibitors",
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).",
keywords = "Class selectivity, Cyclic amide, HDAC, HDAC inhibitor, Hydroxamic acid",
author = "Chihiro Shinji and Satoko Maeda and Keisuke Imai and Minoru Yoshida and Yuichi Hashimoto and Hiroyuki Miyachi",
year = "2006",
month = "11",
day = "15",
doi = "10.1016/j.bmc.2006.07.008",
language = "English",
volume = "14",
pages = "7625--7651",
journal = "Bioorganic and Medicinal Chemistry",
issn = "0968-0896",
publisher = "Elsevier Limited",
number = "22",

}

TY - JOUR

T1 - Design, synthesis, and evaluation of cyclic amide/imide-bearing hydroxamic acid derivatives as class-selective histone deacetylase (HDAC) inhibitors

AU - Shinji, Chihiro

AU - Maeda, Satoko

AU - Imai, Keisuke

AU - Yoshida, Minoru

AU - Hashimoto, Yuichi

AU - Miyachi, Hiroyuki

PY - 2006/11/15

Y1 - 2006/11/15

N2 - 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).

AB - 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).

KW - Class selectivity

KW - Cyclic amide

KW - HDAC

KW - HDAC inhibitor

KW - Hydroxamic acid

UR - http://www.scopus.com/inward/record.url?scp=33749430243&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33749430243&partnerID=8YFLogxK

U2 - 10.1016/j.bmc.2006.07.008

DO - 10.1016/j.bmc.2006.07.008

M3 - Article

C2 - 16877001

AN - SCOPUS:33749430243

VL - 14

SP - 7625

EP - 7651

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

SN - 0968-0896

IS - 22

ER -