Design, Synthesis, and Biological Evaluation of Artemisinin-Piperazine-Phosphoramide Mustard Hybrids as Potential Anticancer Agents.

ChemMedChem

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.

Published: September 2022

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.

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http://dx.doi.org/10.1002/cmdc.202200239DOI Listing

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Design, Synthesis, and Biological Evaluation of Artemisinin-Piperazine-Phosphoramide Mustard Hybrids as Potential Anticancer Agents.

ChemMedChem

September 2022

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.

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.

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