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 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.
Eur J Med Chem. 2019 Jul 15;174:265-276. doi: 10.1016/j.ejmech.2019.04.050. Epub 2019 Apr 21.
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 [IC = 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 G/G 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.
基于天然产物的杂交策略，共设计、合成了 32 种新型的雷公藤红素杂合化合物，并对其抗肿瘤活性进行了评价。与雷公藤红素相比，这些衍生物大多数表现出显著的增殖抑制活性，其中化合物 29 表现出最强的抑制能力[IC=0.15±0.03 μM（A549），0.17±0.03 μM（MCF-7），0.26±0.02 μM（HepG2）]，与 2-氰基-3,12-二氧代齐墩果烷-1,9（11）-二烯-28-酸甲酯（CDDO-Me）相比，具有同等或更好的抗癌活性。药理研究机制表明，29 具有破坏 Hsp90-Cdc37 复合物的能力，其强度强于雷公藤红素。同时，化合物 29 能够以浓度依赖的方式诱导 Hsp90 的客户（p-Akt 和 Cdk4）异常调节和细胞周期停滞在 G/G 期。此外，化合物 29 还可以通过 A549 细胞上的死亡受体途径诱导细胞凋亡。总之，我们的研究结果表明，29 可能是一个有前途的新型候选药物，值得进一步研究。
