2026-08-29T12:38:59Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/255442025-12-18T13:00:53Zcom_20.500.12105_2052com_20.500.12105_2051col_20.500.12105_19617
Repisalud
author
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
funder
Ministerio de Ciencia e Innovación (España)
funder
Comunidad de Madrid (España)
funder
Unión Europea. Comisión Europea. NextGenerationEU
2024-11-20T09:54:30Z
2024-11-20T09:54:30Z
2024-04-25
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
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.
eng
Promising Anticancer Prodrugs Based on Pt(IV) Complexes with Bis-organosilane Ligands in Axial Positions
research article
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PromisingAnticancerProdrugsBased_PtIV _2024.pdf
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