Promising Anticancer Prodrugs Based on Pt(IV) Complexes with Bis-organosilane Ligands in Axial Positions

We report two novel prodrug Pt­(IV) complexes with bis-organosilane ligands in axial positions: cis-dichloro­(diamine)-trans-[3-(triethoxysilyl)­propylcarbamate]­platinum­(IV) (Pt­(IV)-biSi-1) and cis-dichloro­(diisopropylamine)-trans-[3-(triethoxysilyl) propyl carbamate]­platinum­(IV) (Pt­(IV)-biSi-2). Pt­(IV)-biSi-2 demonstrated enhanced in vitro cytotoxicity against colon cancer cells (HCT 116 and HT-29) compared with cisplatin and Pt­(IV)-biSi-1. Notably, Pt­(IV)-biSi-2 exhibited higher cytotoxicity toward cancer cells and lower toxicity on nontumorigenic intestinal cells (HIEC6). In preclinical mouse models of colorectal cancer, Pt­(IV)-biSi-2 outperformed cisplatin in reducing tumor growth at lower concentrations, with reduced side effects. Mechanistically, Pt­(IV)-biSi-2 induced permanent DNA damage independent of p53 levels. DNA damage such as double-strand breaks marked by histone gH2Ax was permanent after treatment with Pt­(IV)-biSi-2, in contrast to cisplatin's transient effects. Pt­(IV)-biSi-2's faster reduction to Pt­(II) species upon exposure to biological reductants supports its superior biological response. These findings unveil a novel strategy for designing Pt­(IV) anticancer prodrugs with enhanced activity and specificity, offering therapeutic opportunities beyond conventional Pt drugs.