Lei Zhi-Chao, Li Na, Yu Nai-Rong, Ju Wei, Sun Xiao-Na, Zhang Xue-Ling, Dong Hai-Juan, Sun Jian-Bo, Chen Li
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.
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.
J Nat Prod. 2022 May 27;85(5):1282-1293. doi: 10.1021/acs.jnatprod.1c01236. Epub 2022 May 10.
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 exhibited the best activity against BGC-823 cells (IC = 0.21 ± 0.01 μM). Further biological studies showed that significantly raised the reactive oxygen species (ROS) levels to activate the apoptotic pathway, causing mitochondrial dysfunction in BGC-823 cells. In addition, also arrested cells in the G2/M phase to induce tumor cell apoptosis. In a nude mouse tumor xenograft model, 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, , and has revealed that increased ROS generation may be an effective strategy in the treatment of GC.
胃癌（GC）是全球常见的恶性疾病，迫切需要寻找治疗GC的新型药物和策略。雷公藤红素（CEL）是一种具有抗肿瘤活性的著名天然产物。在本研究中，在CEL的C-29位引入了吡唑类似物。总共设计、合成了24种新衍生物，并对其体外和体内的作用机制及抗肿瘤活性进行了评估。其中，化合物 对BGC-823细胞表现出最佳活性（IC = 0.21±0.01μM）。进一步的生物学研究表明， 显著提高活性氧（ROS）水平以激活凋亡途径，导致BGC-823细胞线粒体功能障碍。此外， 还使细胞停滞在G2/M期以诱导肿瘤细胞凋亡。在裸鼠肿瘤异种移植模型中， 表现出比CEL更好的肿瘤抑制率（89.85%）（抑制率76.52%）。综上所述，本研究提供了一种抗癌先导化合物候选物 ，并揭示增加ROS生成可能是治疗GC的有效策略。
