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

38 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

Fingerprint

Chaperonin 60
Structure-Activity Relationship
Derivatives
Cells
Cell Line
Penicillium
Growth
Metabolites
Cell Cycle Checkpoints
Ketones
Neuroblastoma
epolactaene
Neoplasms
Esters
Communication

Keywords

  • Chaperone
  • Epolactaene
  • Heat shock protein 60

ASJC Scopus subject areas

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

Cite this

Structure-activity relationships of epolactaene derivatives : Structural requirements for inhibition of Hsp60 chaperone activity. / Nagumo, Yoko; Kakeya, Hideaki; Yamaguchi, Junichiro; Uno, Takao; Shoji, Mitsuru; Hayashi, Yujiro; Osada, Hiroyuki.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 14, No. 17, 06.09.2004, p. 4425-4429.

Research output: Contribution to journalArticle

Nagumo, Yoko ; Kakeya, Hideaki ; Yamaguchi, Junichiro ; Uno, Takao ; Shoji, Mitsuru ; Hayashi, Yujiro ; Osada, Hiroyuki. / Structure-activity relationships of epolactaene derivatives : Structural requirements for inhibition of Hsp60 chaperone activity. In: Bioorganic and Medicinal Chemistry Letters. 2004 ; Vol. 14, No. 17. pp. 4425-4429.
@article{307c13d844514498a84207392a03e1bf,
title = "Structure-activity relationships of epolactaene derivatives: Structural requirements for inhibition of Hsp60 chaperone activity",
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.",
keywords = "Chaperone, Epolactaene, Heat shock protein 60",
author = "Yoko Nagumo and Hideaki Kakeya and Junichiro Yamaguchi and Takao Uno and Mitsuru Shoji and Yujiro Hayashi and Hiroyuki Osada",
year = "2004",
month = "9",
day = "6",
doi = "10.1016/j.bmcl.2004.06.054",
language = "English",
volume = "14",
pages = "4425--4429",
journal = "Bioorganic and Medicinal Chemistry Letters",
issn = "0960-894X",
publisher = "Elsevier Limited",
number = "17",

}

TY - JOUR

T1 - Structure-activity relationships of epolactaene derivatives

T2 - Structural requirements for inhibition of Hsp60 chaperone activity

AU - Nagumo, Yoko

AU - Kakeya, Hideaki

AU - Yamaguchi, Junichiro

AU - Uno, Takao

AU - Shoji, Mitsuru

AU - Hayashi, Yujiro

AU - Osada, Hiroyuki

PY - 2004/9/6

Y1 - 2004/9/6

N2 - 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.

AB - 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.

KW - Chaperone

KW - Epolactaene

KW - Heat shock protein 60

UR - http://www.scopus.com/inward/record.url?scp=3843120076&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=3843120076&partnerID=8YFLogxK

U2 - 10.1016/j.bmcl.2004.06.054

DO - 10.1016/j.bmcl.2004.06.054

M3 - Article

C2 - 15357965

AN - SCOPUS:3843120076

VL - 14

SP - 4425

EP - 4429

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

SN - 0960-894X

IS - 17

ER -