Structure-activity relationships of epolactaene derivatives: Structural requirements for inhibition of Hsp60 chaperone activity

Yoko Nagumo, Hideaki Kakeya, Junichiro Yamaguchi, Takao Uno, Mitsuru Shoji, Yujiro Hayashi, Hiroyuki Osada

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Epolactaene derivatives were synthesized and their ability to inhibit the growth of human cancer cell lines was tested. These derivatives were further analyzed for their ability to affect human heat shock protein 60 (Hsp60). We discovered the structural characteristics important for the ability to bind to Hsp60 and the fundamental role of α,β-unsaturated ketone in inhibiting Hsp60 chaperone activity. Epolactaene is a microbial metabolite isolated from the fungal strain Penicillium sp. It arrests the cell cycle at the G 0/G 1 phase and induces the outgrowth of neurites in human neuroblastoma SH-SY5Y cells. In this communication, we report the structure-activity relationships (SARs) of new epolactaene derivatives, including those lacking the epoxylactam moiety and having various side chains. These derivatives were evaluated for their ability to inhibit the growth of human cancer cell lines. They were also analyzed for their ability to affect human heat shock protein 60 (Hsp60), which we have already identified as a protein that binds to epolactaene. We also identified the important structural framework of epolactaene/ETB (epolactaene tertiary butyl ester) for not only binding to Hsp60 but also inhibiting Hsp60 chaperone activity.

Original languageEnglish
Pages (from-to)4425-4429
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume14
Issue number17
DOIs
Publication statusPublished - 2004 Sep 6
Externally publishedYes

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Keywords

  • Chaperone
  • Epolactaene
  • Heat shock protein 60

ASJC Scopus subject areas

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

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