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

Recently,artemisinin and derivatives have been revealedto possessencouraging antitumor activity. Herein, we integrated the antitumoradvantages of artesunate and platinum drugs to construct novel Pt-IV-artesunate dual-action and triple-action complexes.Most derivatives, especially 10f, displayed broad-spectrumand potent in vitro antitumor activities againsta number of cancer cell lines. Compound 10f displayedpotent antimetastasis and anticlonogenic activities, efficiently inducedautophagic cell death and apoptosis, and arrested the cell cycle atboth S and G2/M phases. More importantly, it displayed remarkable in vivo antitumor efficacy in the A549 xenograft model (TGI= 53.4%; 6 mu mol/kg) with low toxicity. In addition to the antitumorapplication, 10f showed potent in vivo antimalarial activity in malarial-infected mice model and obviouslyalleviated malarial-related multiorgan injury. This conjugation greatlyimproved safety, especially reducing the platinum drugs' nephrotoxicity.Taken together, this study highlighted the therapeutic potential ofPt(IV)-artesunate complexes as antitumor and antimalarialagents.

Automated summary

Recently, the antitumor activity of artemisinin and its derivatives has been discovered. This study constructed novel Pt-IV-artesunate complexes to combine the antitumor advantages of artesunate and platinum drugs. The derivatives, especially 10f, exhibited potent in vitro antitumor activities against various cancer cell lines. Compound 10f demonstrated remarkable in vivo antitumor efficacy in a xenograft model, and also showed potent in vivo antimalarial activity. This study highlights the therapeutic potential of Pt(IV)-artesunate complexes as antitumor and antimalarial agents.