Key Laboratory of Advanced Drug Preparation Technologies (Zhengzhou University), Ministry of Education, PR China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, PR China; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China; Key Laboratory of Henan Province for Drug Quality and Evaluation, PR China.
Key Laboratory of Advanced Drug Preparation Technologies (Zhengzhou University), Ministry of Education, PR China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, PR China; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China; Key Laboratory of Henan Province for Drug Quality and Evaluation, PR China.
Eur J Med Chem. 2018 Feb 10;145:11-22. doi: 10.1016/j.ejmech.2017.12.094. Epub 2018 Jan 2.
A series of new steroidal pyridines have been synthesized through the based-promoted three-component reaction and preliminarily evaluated for their antiproliferative activity against different types of cancer cell lines. SARs studies showed that the heterocyclic rings attached to the 4-position of the pyridine ring were preferred over the phenyl rings for the activity. Among these compounds, the most potent compound exhibited good growth inhibition against all the tested cancer cells, especially for PC-3 cells with an IC value of 1.55 μM. Further mechanistic studies revealed that the most potent compound inhibited colony formation, migration and evasion of PC-3 cells in a concentration-dependent manner as well as induced apoptosis of PC-3 cells possibly through the mitochondria-related apoptotic pathways. Caspase-3/-9 and PARP were activated, finally leading to the apoptosis of PC-3 cells. For the androgen-sensitive (AR) prostate cancer cell line LNCaP, the most potent compound was less potent than abiraterone with the IC value of 8.48 and 3.29 μM, respectively. The most potent compound could be used as a starting point for the development of new steroidal heterocycles with improved anticancer potency and selectivity. The synthesized steroidal pyridines contain the functional -OEt and CN groups, which could be used for further modifications for the construction of the steroid library.
一系列新的甾体吡啶类化合物通过基于碱促进的三组分反应合成，并初步评估了它们对不同类型癌细胞系的抗增殖活性。SARs 研究表明，与苯环相比，吡啶环 4 位连接的杂环更有利于活性。在这些化合物中，最有效的化合物对所有测试的癌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 1.55 μM。进一步的机制研究表明，最有效的化合物以浓度依赖的方式抑制 PC-3 细胞的集落形成、迁移和逃逸，以及通过线粒体相关的凋亡途径诱导 PC-3 细胞凋亡。Caspase-3/-9 和 PARP 被激活，最终导致 PC-3 细胞凋亡。对于雄激素敏感 (AR) 前列腺癌细胞系 LNCaP，最有效的化合物的活性不如阿比特龙，IC 值分别为 8.48 和 3.29 μM。最有效的化合物可以作为开发具有更高抗癌活性和选择性的新型甾体杂环的起点。合成的甾体吡啶含有功能 -OEt 和 CN 基团，可用于进一步修饰以构建甾体文库。
