Design, synthesis, and antitumor activity of matrine aminophosphonate derivatives as potent mcl-1 inhibitors

A series of novel matrine aminophosphonate derivatives were designed and synthesized to explore more efficacious and less toxic Mcl-1 inhibitors, following the principle of combination and hybridization. The representative compound, 9 k, exhibited more potent cytotoxicity against human cervical cancer cells compared to the positive control 5-FU. A molecular docking study was also conducted to understand the interactions of 9 k with the Mcl-1 protein. Mechanistic studies revealed that compound 9 k could induce apoptosis in Hela cells, accompanied by changes in chromatin morphology, an elevation of intracellular ROS levels, and the dissipation of MMP. Notably, in vivo studies indicated that 9 k inhibited tumor growth in a Hela xenograft model. In summary, this study suggests that compound 9 k represents a potent and selective Mcl-1 inhibitor for the treatment of human cervical cancer.