An oxadiazole Pt(II) complex with promising in vivo antitumor activity

This study aims at the identification of an effective and safe platinum(II)-based anticancer drug characterized by a dual mechanism of action: interference with DNA replication and inhibition of STAT3 signaling pathway. On the base of the emerging connection between these chemotherapic agents and STAT31-3 and the role of the oxadiazole ring in anticancer drug design4,5, we synthesized 3-aminomethyl-1,2,5-oxadiazole derivatives as ligands in dichloride Pt(II) complexes.Ligands expressed a negligible (1 and 2) or weak (3) antiproliferative activity in the MTT assay on HCT116 cancer cell line, while their coordination to platinum resulted in an increased cytotoxicity (in particular Pt-3 displayed the lowest IC50 value, 18.4 µM). The effect on STAT3 dimerization was evaluated by an in vitro competitive binding assay, the AlphaScreen-based assay: 1 and 2 were inactive, while 3 highlighted interesting STAT3 inhibitory properties, disrupting STAT3 dimerization in a selective manner with respect to STAT1. Also in this case the coordination to platinum resulted in an increased inhibitory activity. These preliminary data led us to focus on 3 and Pt-3 which underwent in vivo studies showing a reduction of the tumor mass similarly to cisplatin but with no body weight changes (despite the higher dose compared to cisplatin). Finally, we are deeply investigating the molecular mechanism and evaluating the antiproliferative activity on cell lines poorly sensitive to cisplatin.