Discovery of PlatinumIV–Artesunate Multiaction Prodrugs as Potent Antitumor and Antimalarial Agents

Recently, artemisinin and derivatives have been revealed to possess encouraging antitumor activity. Herein, we integrated the antitumor advantages of artesunate and platinum drugs to construct novel PtIV–artesunate dual-action and triple-action complexes. Most derivatives, especially 10f, displayed broad-spectrum and potent in vitro antitumor activities against a number of cancer cell lines. Compound 10f displayed potent antimetastasis and anticlonogenic activities, efficiently induced autophagic cell death and apoptosis, and arrested the cell cycle at both S and G2/M phases. More importantly, it displayed remarkable in vivo antitumor efficacy in the A549 xenograft model (TGI = 53.4%; 6 μmol/kg) with low toxicity. In addition to the antitumor application, 10f showed potent in vivo antimalarial activity in malarial-infected mice model and obviously alleviated malarial-related multiorgan injury. This conjugation greatly improved safety, especially reducing the platinum drugs’ nephrotoxicity. Taken together, this study highlighted the therapeutic potential of PtIV–artesunate complexes as antitumor and antimalarial agents.