Hu Xu, Wang Yan, Xue Jingjing, Han Tong, Jiao Runwei, Li Zhanlin, Liu Weiwei, Xu Fanxing, Hua Huiming, Li Dahong
Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China.
Valiant Co. Ltd., 11 Wuzhishan Road, YEDA Yantai, Shandong 264006, PR China.
Bioorg Med Chem Lett. 2017 Nov 15;27(22):4989-4993. doi: 10.1016/j.bmcl.2017.10.014. Epub 2017 Oct 7.
A series of novel nitrogen mustard-evodiamine hybrids were synthesized and evaluated for their antitproliferative properties. The antiproliferative activities of 10a-d, 11a-d, and 12a-d against four different kinds of human cancer cell lines (PC-3, HepG2, THP-1 and HL-60) and human normal peripheral blood mononuclear cells (PBMC) were determined. The results showed that all the target hybrid compounds exhibited antiproliferative activities against tested human tumor cell lines to some extent and no antiproliferative activities (>200 μM) against human normal PBMC cells. The antiproliferative selectivity between tumorous and normal cells was very useful for further antitumor drug development. Among the target compounds, 12c showed the strongest cytotoxicity against two tumor cell lines (THP-1 and HL-60) with IC values of 4.05 μM and 0.50 μM, respectively, and selected for further mechanism study in HL-60 cells. The results showed that 12c could induce HL-60 cells apoptosis and arrest at G phase at low sub-micromolar concentrations via mitochondria-related pathways.
合成了一系列新型氮芥-吴茱萸碱杂合物，并对其抗增殖特性进行了评估。测定了10a-d、11a-d和12a-d对四种不同人类癌细胞系（PC-3、HepG2、THP-1和HL-60）以及人类正常外周血单个核细胞（PBMC）的抗增殖活性。结果表明，所有目标杂合物对受试人类肿瘤细胞系均表现出一定程度的抗增殖活性，而对人类正常PBMC细胞无抗增殖活性（>200μM）。肿瘤细胞与正常细胞之间的抗增殖选择性对进一步开发抗肿瘤药物非常有用。在目标化合物中，12c对两种肿瘤细胞系（THP-1和HL-60）表现出最强的细胞毒性，IC值分别为4.05μM和0.50μM，并被选用于HL-60细胞的进一步机制研究。结果表明，12c可在低微摩尔浓度下通过线粒体相关途径诱导HL-60细胞凋亡并使其停滞在G期。
