2. Academic Validation
  3. Design and Synthesis of Novel Celastrol Derivatives as Potential Anticancer Agents against Gastric Cancer Cells

Design and Synthesis of Novel Celastrol Derivatives as Potential Anticancer Agents against Gastric Cancer Cells

  • J Nat Prod. 2022 May 27;85(5):1282-1293. doi: 10.1021/acs.jnatprod.1c01236.
Zhi-Chao Lei 1,  Na Li 1 2,  Nai-Rong Yu 1,  Wei Ju 1,  Xiao-Na Sun 1,  Xue-Ling Zhang 1,  Hai-Juan Dong 3,  Jian-Bo Sun 1,  Li Chen 1 4
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 Breeding Base-Hebei Province Key Laboratory of Molecular Chemistry for Drug, Hebei University of Science & Technology, 26 Yuxiang Street, Hebei 050018, People's Republic of China.
  • 3 The Public Laboratory Platform, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.
  • 4 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, 132 Lanhei Road, Kunming 650201, Yunnan, People's Republic of China.
PMID: 35536757 DOI: 10.1021/acs.jnatprod.1c01236
Abstract

Gastric Cancer (GC) is a common malignant disease worldwide, and finding novel agents and strategies for the treatment of GC are of urgent need. Celastrol (CEL) is a well-known natural product with antineoplastic activity. In this study, pyrazole analogues were introduced at the C-29 position of CEL. A total of 24 new derivatives were designed, synthesized, and evaluated for their mechanism and antitumor activity in vitro and in vivo. Among them, compound 21 exhibited the best activity against BGC-823 cells (IC50 = 0.21 ± 0.01 μM). Further biological studies showed that 21 significantly raised the Reactive Oxygen Species (ROS) levels to activate the apoptotic pathway, causing mitochondrial dysfunction in BGC-823 cells. In addition, 21 also arrested cells in the G2/M phase to induce tumor cell Apoptosis. In a nude mouse tumor xenograft model, 21 exhibited a better tumor inhibition rate (89.85%) than CEL (inhibition rate 76.52%). Taken together, the present study has provided an Anticancer lead compound candidate, 21, and has revealed that increased ROS generation may be an effective strategy in the treatment of GC.

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