Synthesis and Biological Evaluation of Celastrol Derivatives with Improved Cytotoxic Selectivity and Antitumor Activities

  • J Nat Prod. 2021 Jul 23;84(7):1954-1966. doi: 10.1021/acs.jnatprod.1c00262.
Xiao-Long Hu  1 ,  Qi-Wei He  1 ,  Huan Long  1 ,  Li-Xin Zhang  1 ,  Rong Wang  1 ,  Bao-Lin Wang  1 ,  Jia-Hao Feng  1 ,  Quan Wang  1 ,  Ji-Qin Hou  1 ,  Xiao-Qi Zhang  2 ,  Wen-Cai Ye  2 ,  Hao Wang  1
Affiliations
  • 1. State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
  • 2. Institute of Traditional Chinese Medicine and Natural Products, Jinan University, Guangzhou 510632, People's Republic of China.
PMID: 34170694 DOI: 10.1021/acs.jnatprod.1c00262
Abstract

Cdc37 associates kinase clients to HSP90 and promotes the development of cancers. Celastrol, a natural friedelane triterpenoid, can disrupt the Hsp90-Cdc37 interaction to provide antitumor effects. In this study, 31 new celastrol derivatives, 2a-2d, 3a-3g, and 4a-4t, were designed and synthesized, and their Hsp90-Cdc37 disruption activities and antiproliferative activities against Cancer cells were evaluated. Among these compounds, 4f, with the highest tumor cell selectivity (15.4-fold), potent Hsp90-Cdc37 disruption activity (IC50 = 1.9 μM), and antiproliferative activity against MDA-MB-231 cells (IC50 = 0.2 μM), was selected as the lead compound. Further studies demonstrated 4f has strong antitumor activities both in vitro and in vivo through disrupting the Hsp90-Cdc37 interaction and inhibiting angiogenesis. In addition, 4f exhibited less toxicity than celastrol and showed a good pharmacokinetics profile in vivo. These findings suggest that 4f may be a promising candidate for development of new Cancer therapies.