School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.
School of Nursing, Guangzhou University of Chinese Medicine, Guangzhou, China.
Arch Pharm (Weinheim). 2021 Jun;354(6):e2000448. doi: 10.1002/ardp.202000448. Epub 2021 Mar 1.
Continuing our studies on NO-donating ursolic acid-benzylidene derivatives as potential antitumor agents, we designed and synthesized a series of new arylidene derivatives containing NO-donating ursolic acid and aromatic heterocyclic units. Compounds 5c and 6c showed a significant broad-spectrum antitumor activity. Compound 5c exhibited nearly three- to nine-fold higher cytotoxicity as compared with the parent drug in A549, MCF-7, HepG-2, HT-29, and HeLa cells, and it was also found to be the most potent apoptosis inducer of MCF-7 cells. More importantly, compound 5c arrested the MCF-7 cell cycle in the G1 phase, which was associated with caspase activation and a decrease of the Bcl-2/Bax ratio. Meanwhile, compound 5c caused changes in morphological features, dissipation of the mitochondrial membrane potential, and accumulation of reactive oxygen species. A docking study revealed that the nitroxyethyl moiety of compound 5c may form hydrogen bonds with caspase-8 amino acid residues (SER256 and HIS255). Together, these data suggest that NO-donating ursolic acid-arylidene derivatives are potent apoptosis inducers in tumor cells.
我们继续研究作为潜在抗肿瘤药物的一氧化氮供体型熊果酸苄叉衍生物，设计并合成了一系列含有一氧化氮供体熊果酸和芳杂环单元的新型芳叉衍生物。化合物 5c 和 6c 表现出显著的广谱抗肿瘤活性。与母体药物相比，化合物 5c 在 A549、MCF-7、HepG-2、HT-29 和 HeLa 细胞中的细胞毒性提高了近 3 到 9 倍，并且被发现是 MCF-7 细胞中最强的凋亡诱导剂。更重要的是，化合物 5c 将 MCF-7 细胞周期阻滞在 G1 期，这与半胱天冬酶的激活和 Bcl-2/Bax 比值的降低有关。同时，化合物 5c 引起细胞形态特征的改变、线粒体膜电位的耗散和活性氧的积累。对接研究表明，化合物 5c 的硝氧乙基部分可能与半胱天冬酶-8 氨基酸残基（SER256 和 HIS255）形成氢键。综上所述，这些数据表明，一氧化氮供体型熊果酸芳叉衍生物是肿瘤细胞中有效的凋亡诱导剂。
