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

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 IC50 (HEK‐293T)/IC50 (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. Twelve novel artemisinin‐piperazine‐phosphoramide mustard (PPM) hybrids 7 a–l were synthesized via an efficient, catalyst‐free two‐step sequential substitution. Artemisinin‐PPM hybrids 7 showed better cytotoxicity than DHA and VCR. Cytotoxicity was significantly enhanced by the introduction of a thiazole moiety. Hybrid 7 h displayed 7.4‐fold stronger potency than VCR, and is both the most potent compound synthesised, and the most selective (selectivity index=16).