Wang Wenbao, Zhang Yingying, Yao Guodong, Wang Wei, Shang Xinyue, Zhang Yan, Wang Xiaobo, Wang Shaojie, Song Shaojiang
Department of Natural Products Chemistry, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China; Key Laboratory of Structure-Based Drug Design & Discovery (Ministry of Education), Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
Department of Natural Products Chemistry, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China; Key Laboratory of Structure-Based Drug Design & Discovery (Ministry of Education), Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China; Chinese People's Liberation Army 210 Hospital, Dalian 116021, People's Republic of China.
Steroids. 2018 Mar;131:23-31. doi: 10.1016/j.steroids.2018.01.001. Epub 2018 Jan 11.
Sarsasapogenin, a kind of mainly effective component of Anemarrhena asphodeloides Bunge, possesses good antitumor properties. Two series of new sarsasapogenin derivatives were synthesized and evaluated for their cytotoxicities against three human cancer cell lines (HepG2, A549, MCF-7) using the MTT assay. The structure-activity relationship revealed that the N, N-dimethylamino, pyrrolidinyl, and imidazolyl substituted at the C26 position could increase the antitumor efficacy of the 3-oxo sarsasapogenin series of compounds. Compound 4c with pyrrolidinyl substituted at the C26 position exhibited the greatest cytotoxic activity against MCF-7 cell line (IC = 10.66 μM), which was 4.3-fold more potent than sarsasapogenin. Action mechanism investigations showed that 4c could inhibit the colony formation and induce the apoptosis of MCF-7 cells. Further researches showed that a decrease in mitochondrial membrane potential and increases in the expression level of cleaved-PARP and the ratio of Bax/Bcl-2 were observed in MCF-7 cells after treatment with 4c, suggesting that the mitochondrial pathway was involved in the 4c-mediated apoptosis. These results show that compound 4c may serve as a lead for further optimization.
知母皂苷元是知母的一种主要有效成分，具有良好的抗肿瘤特性。合成了两个系列的新型知母皂苷元衍生物，并使用MTT法评估了它们对三种人类癌细胞系（HepG2、A549、MCF-7）的细胞毒性。构效关系表明，在C26位取代的N，N-二甲基氨基、吡咯烷基和咪唑基可提高3-氧代知母皂苷元系列化合物的抗肿瘤功效。在C26位被吡咯烷基取代的化合物4c对MCF-7细胞系表现出最大的细胞毒性活性（IC = 10.66 μM），其效力比知母皂苷元高4.3倍。作用机制研究表明，4c可抑制MCF-7细胞的集落形成并诱导其凋亡。进一步研究表明，用4c处理后的MCF-7细胞中线粒体膜电位降低，裂解的PARP表达水平升高以及Bax/Bcl-2比值增加，这表明线粒体途径参与了4c介导的凋亡。这些结果表明化合物4c可作为进一步优化的先导化合物。
