2. Academic Validation
  3. Elucidation of structure-activity relationship of humulanolides and identification of humulanolide analog as a novel HSP90 inhibitor

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

  • Bioorg Med Chem Lett. 2022 Mar 15:60:128589. doi: 10.1016/j.bmcl.2022.128589.
Junya Saegusa 1,  Yoshiyuki Osada 1,  Kazuki Miura 1,  Yukiko Sasazawa 1,  Akihiro Ogura 1,  Ken-Ichi Takao 1,  Siro Simizu 2
Affiliations

Affiliations

  • 1 Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan.
  • 2 Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan. Electronic address: [email protected].
PMID: 35093502 DOI: 10.1016/j.bmcl.2022.128589
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.

Keywords

Anti-proliferative activity; HSP90 inhibitor; Humulanolides; Natural products; Structure-activity relationship.

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