2. Academic Validation
  3. Design, synthesis and biological evaluation of a new class of Hsp90 inhibitors vibsanin C derivatives

Design, synthesis and biological evaluation of a new class of Hsp90 inhibitors vibsanin C derivatives

  • Eur J Med Chem. 2022 Dec 15;244:114844. doi: 10.1016/j.ejmech.2022.114844.
Meng Li 1,  Xianlan She 1,  Yufei Ou 1,  Jiangxin Liu 2,  Zaifeng Yuan 3,  Qin-Shi Zhao 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 2 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China. Electronic address: liujiangxin@mail.kib.ac.cn.
  • 3 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China. Electronic address: zaifengyuan@mail.kib.ac.cn.
  • 4 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China. Electronic address: qinshizhao@mail.kib.ac.cn.
PMID: 36274275 DOI: 10.1016/j.ejmech.2022.114844
Abstract

HSP90, an ATP-dependent chaperone that is essential for a wide range of protein assembly and folding processes, has long been recognized as a potential target for Cancer. HSP90 has more recently been identified as having a significant pathogenic role in viral Infection, neurodegenerative disease, and inflammation, therefore, the development of the agents to inhibit the chaperone could potentially treat such intractable diseases. Here, on the basis of primary structure-activity relationships and docking analysis, a series of novel vibsanin C analogues with an emphasis on the C18 position was first designed, synthesized and biologically evaluated. The most effective HSP90 inhibitory activity among these analogues was demonstrated by 29 and 31, with IC50 values of 0.39 and 0.27 μM respectively. Direct interaction between HSP90 and its inhibitors were further confirmed. Mechanism studies indicated that 29 promoted HL-60 cell Apoptosis by mitochondrial-mediated Apoptosis pathway. In addition, 29 suppressed tumor growth in the H22 tumor-bearing mice model and revealed low acute toxicity in mice (LD50 > 500 mg/kg), suggesting its potential for further investigations.

Keywords

Antitumor; Hsp90 inhibitor; Natural product; Vibsanin C.

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