2026-08-29T14:05:00Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/255442025-12-18T13:00:53Zcom_20.500.12105_2052com_20.500.12105_2051col_20.500.12105_19617

00925njm 22002777a 4500 dc Navas, Francisco author Chocarro-Calvo, Ana author Iglesias-Hernandez, Patricia author Iglesias-Hernandez, Patricia author Fernández-García, Paloma author Morales, Victoria author García-Martínez, José Manuel author Sanz, Raúl author De la Vieja, Antonio author García-Jiménez, Custodia author García-Muñoz, Rafael A author 2024-04-25 We report two novel prodrug Pt(IV) complexes with bis-organosilane ligands in axial positions: -dichloro(diamine)--[3-(triethoxysilyl)propylcarbamate]platinum(IV) (Pt(IV)-biSi-1) and -dichloro(diisopropylamine)--[3-(triethoxysilyl) propyl carbamate]platinum(IV) (Pt(IV)-biSi-2). Pt(IV)-biSi-2 demonstrated enhanced 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. J Med Chem. 2024 Apr 25;67(8):6410-6424. 10.1021/acs.jmedchem.3c02393 1520-4804 0022-2623 Journal of medicinal chemistry 38592014 https://hdl.handle.net/20.500.12105/25544 Promising Anticancer Prodrugs Based on Pt(IV) Complexes with Bis-organosilane Ligands in Axial Positions