Wei Meng-Xue, Zhang Si-Si, Sun Xuanrong, Ji Yang, Yang Pei-Wen, Li Xue-Qiang
State Key Laboratory of High-efficiency Utilization of Coal and Green Chemical Engineering, National Demonstration Center for Experimental Chemistry Education, College of Chemistry and Chemical Engineering, Ningxia University, 489 Helanshan West Road, 750021, Yinchuan, China.
Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, OX1 3TA, Oxford, UK.
ChemMedChem. 2022 Sep 5;17(17):e202200239. doi: 10.1002/cmdc.202200239. Epub 2022 Jul 13.
A series of novel artemisinin-piperazine-phosphoramide mustard (PPM) hybrids were designed and synthesized by incorporating phosphoramide mustard (PM) into dihydroartemisinin (DHA) via an efficient, catalyst-free two-step sequential substitution. Artemisinin-PPM hybrids showed better cytotoxic potency against HepG2 cells than both the parent DHA and the reference, vincristine (VCR). Structure-activity relationship (SAR) studies showed that the cytotoxicity was significantly enhanced by the introduction of a thiazole moiety. Hybrid 7 h, the most potent compound with the highest selectivity index IC (HEK-293T)/IC (HepG2)=16, displayed 7.4-fold stronger potency than VCR against HepG2 cells. In addition, hybrid 7 h was substantially more cytotoxic on all human cancer cells tested than on the corresponding non-cancerous cells. Flow cytometric analysis showed that 7 h significantly blocked the cell cycle in the G0/G1 phase and induced apoptosis in a concentration-dependent manner.
通过高效、无催化剂的两步连续取代反应，将磷酰胺氮芥（PM）引入双氢青蒿素（DHA）中，设计并合成了一系列新型青蒿素-哌嗪-磷酰胺氮芥（PPM）杂合物。青蒿素-PPM杂合物对肝癌细胞HepG2的细胞毒性比母体DHA和参考药物长春新碱（VCR）更强。构效关系（SAR）研究表明，噻唑部分的引入显著增强了细胞毒性。杂合物7h是最具活性的化合物，其选择性指数IC（HEK-293T）/IC（HepG2）=16，对HepG2细胞的活性比VCR强7.4倍。此外，杂合物7h对所有测试的人类癌细胞的细胞毒性均显著高于相应的非癌细胞。流式细胞术分析表明，7h显著阻断细胞周期于G0/G1期，并以浓度依赖的方式诱导细胞凋亡。
