Elucidation of structure-activity relationship of humulanolides and identification of humulanolide analog as a novel HSP90 inhibitor

Junya Saegusa, Yoshiyuki Osada, Kazuki Miura, Yukiko Sasazawa, Akihiro Ogura, Ken ichi Takao, Siro Simizu

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Humulanolides are natural products isolated from Asteriscus, and the isolation and total synthesis of many types of humulanolides have been reported. In this study, we evaluated anti-proliferative activity of twelve humulanolides against various human cancer cell lines and found that humulanolide analog E, which was newly designed and synthesized, exhibited the highest anti-proliferative activity. Structure-activity relationship analysis revealed that α,β-unsaturated carbonyl moieties in humulanolides play an important role for anti-proliferative activity. To identify molecular targets of humulanolide analog E, we investigated various cell-based and in vitro assays. Treatment with humulanolide analog E against human fibrosarcoma HT1080 cells increased the expression level of HSP70 protein and decreased the levels of AKT and CDK4, which are HSP90 client proteins. Moreover, humulanolide analog E inhibited refolding of denatured luciferase protein via suppression of HSP90 activity in vitro. These results suggest that humulanolide analog E possesses the anti-proliferative activity against human cancer cells by inhibiting HSP90 functions.

Original languageEnglish
Article number128589
JournalBioorganic and Medicinal Chemistry Letters
Volume60
DOIs
Publication statusPublished - 2022 Mar 15

Keywords

  • Anti-proliferative activity
  • HSP90 inhibitor
  • Humulanolides
  • Natural products
  • Structure-activity relationship

ASJC Scopus subject areas

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

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