2. Academic Validation
  3. Design, synthesis and antitumor evaluation of novel celastrol derivatives

Design, synthesis and antitumor evaluation of novel celastrol derivatives

  • Eur J Med Chem. 2019 Jul 15:174:265-276. doi: 10.1016/j.ejmech.2019.04.050.
Manyi Xu 1,  Na Li 1,  Zihao Zhao 1,  Zhixian Shi 1,  Jianbo Sun 2,  Li Chen 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, People's Republic of China.
  • 2 State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, People's Republic of China. Electronic address: sunjianbo@cpu.edu.cn.
  • 3 State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, People's Republic of China. Electronic address: chenli627@cpu.edu.cn.
PMID: 31051401 DOI: 10.1016/j.ejmech.2019.04.050
Abstract

On the basis of the hybridization strategy of Natural Products, a total of 32 novel celastrol hybrids were designed, synthesized and evaluated for their antitumor activities. Most of these derivatives exihibited significant antiproliferative activities compared to celastrol, among which compound 29 displayed the strongest inhibitory capability [IC50 = 0.15 ± 0.03 μM (A549),0.17 ± 0.03 μM (MCF-7), 0.26 ± 0.02 μM (HepG2)], which exhibited equal or superior anti-cancer activities in comparison to 2-cyano-3,12-dioxoolean-1,9 (11)-dien-28-oic acid methyl ester (CDDO-Me). The mechanism of pharmacological research indicated that 29 possessed the ability to disrupt Hsp90-Cdc37 complex which was stronger than celastrol. Meanwhile, compound 29 could induce abnormal regulation of clients (p-Akt and CDK4) of HSP90 and cell cycle arrest at G0/G1 phase in a concentration-dependent manner. In addition, compound 29 could also induce cell Apoptosis through the death receptor pathway on A549 cells. Taken together, our results demonstrated that 29 might be a promising novel candidate for further druggability research.

Keywords

Anti-tumor; Apoptosis; Celastrol; Ferulic acid; Hybridization.

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