Elucidation of structure-activity relationship of humulanolides and identification of humulanolide analog as a novel HSP90 inhibitor. (15th March 2022)

• Record Type: Journal Article
• Authors: Saegusa, Junya; Osada, Yoshiyuki; Miura, Kazuki; Sasazawa, Yukiko; Ogura, Akihiro; Takao, Ken-ichi; Simizu, Siro
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 60(2022)
• Publication Date: 2022-03-15
• Subjects: Natural products -- Humulanolides -- Structure-activity relationship -- Anti-proliferative activity -- HSP90 inhibitor; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2022.128589
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: α, β-unsaturated carbonyl moieties in humulanolides play an important role for anti-proliferative activity. Humulanolide analog E is a novel HSP90 inhibitor. Inhibition of HSP90 function would be responsible for anti-proliferative activity of humulanolide analog E. 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.