Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, China.
Taiyuan Central Hospital of Shanxi Medical University, No. 5, Dong San Dao Xiang, Jiefang Road, Taiyuan 030009, China.
Steroids. 2021 Jul;171:108841. doi: 10.1016/j.steroids.2021.108841. Epub 2021 Apr 24.
A series of new 17-cyanopyridine derivatives of pregnenolone have been synthesized, and their anti-proliferative activities against different human cancer cell lines were tested. The extensive structure-activity relationship (SAR) data suggested that the introduction of 2-amino-4-aryl-3-cyanopyridine to the D ring of pregnenolone may increase the anti-cancer activity. Among the products, the most potent compound 4j exhibited good growth inhibition against all the tested cells especially for PC- 3 cells with an IC value of 2.0 μM. Further mechanistic studies showed that 4j inhibited the formation of cell colonies and migration, increased the level of reactive oxygen species (ROS) in PC-3 cells in a concentration-dependent manner, and induced necroptosis through the phosphorylation of receptor interacting protein 1/3 (P-RIP1/3) and phosphorylation of mixed lineage kinase domain-like protein (P-MLKL) pathway. The 17-pregnenolone cyanopyridine derivatives hold promising potential as anti-proliferative agents, and the most potent compound could be used as a starting point for the development of new steroidal heterocycles with improved anticancer potency and selectivity.
已合成了一系列新的孕烯醇酮 17-氰基吡啶衍生物，并测试了它们对不同人癌细胞系的抗增殖活性。广泛的构效关系（SAR）数据表明，将 2-氨基-4-芳基-3-氰基吡啶引入孕烯醇酮的 D 环可能会增加抗癌活性。在这些产物中，最有效的化合物 4j 对所有测试的细胞均表现出良好的生长抑制作用，特别是对 PC-3 细胞的 IC 值为 2.0 μM。进一步的机制研究表明，化合物 4j 以浓度依赖的方式抑制细胞集落的形成和迁移，增加 PC-3 细胞中活性氧（ROS）的水平，并通过受体相互作用蛋白 1/3（P-RIP1/3）的磷酸化和混合谱系激酶结构域样蛋白（P-MLKL）途径诱导坏死性凋亡。17-孕烯醇酮氰基吡啶衍生物具有作为增殖抑制剂的巨大潜力，最有效的化合物可作为开发具有改善抗癌效力和选择性的新型甾体杂环的起点。
