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Promising Anticancer Prodrugs Based on Pt(IV) Complexes with Bis-organosilane Ligands in Axial Positions.
Navas, Francisco; Chocarro-Calvo, Ana; Iglesias-Hernández, Patricia; Fernández-García, Paloma; Morales, Victoria; García-Martínez, José Manuel; Sanz, Raúl; De la Vieja, Antonio; García-Jiménez, Custodia; García-Muñoz, Rafael A.
Afiliación
  • Navas F; Group of Chemical and Environmental Engineering, Rey Juan Carlos University. C/Tulipán s/n, Móstoles, Madrid28933, Spain.
  • Chocarro-Calvo A; Department of Basic Health Sciences. Rey Juan Carlos University. Avda. Atenas s/n, Alcorcón, Madrid 28922, Spain.
  • Iglesias-Hernández P; Endocrine Tumor Unit Chronic Disease Program (UFIEC). Carlos III Health Institute. Ctra. Majadahonda a Pozuelo km 2,2. Majadahonda, Madrid 28220, Spain.
  • Fernández-García P; Group of Chemical and Environmental Engineering, Rey Juan Carlos University. C/Tulipán s/n, Móstoles, Madrid28933, Spain.
  • Morales V; Group of Chemical and Environmental Engineering, Rey Juan Carlos University. C/Tulipán s/n, Móstoles, Madrid28933, Spain.
  • García-Martínez JM; Department of Basic Health Sciences. Rey Juan Carlos University. Avda. Atenas s/n, Alcorcón, Madrid 28922, Spain.
  • Sanz R; Group of Chemical and Environmental Engineering, Rey Juan Carlos University. C/Tulipán s/n, Móstoles, Madrid28933, Spain.
  • De la Vieja A; Endocrine Tumor Unit Chronic Disease Program (UFIEC). Carlos III Health Institute. Ctra. Majadahonda a Pozuelo km 2,2. Majadahonda, Madrid 28220, Spain.
  • García-Jiménez C; Department of Basic Health Sciences. Rey Juan Carlos University. Avda. Atenas s/n, Alcorcón, Madrid 28922, Spain.
  • García-Muñoz RA; Group of Chemical and Environmental Engineering, Rey Juan Carlos University. C/Tulipán s/n, Móstoles, Madrid28933, Spain.
J Med Chem ; 67(8): 6410-6424, 2024 Apr 25.
Article en En | MEDLINE | ID: mdl-38592014
ABSTRACT
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Compuestos Organoplatinos / Profármacos / Antineoplásicos Límite: Animals / Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2024 Tipo del documento: Article País de afiliación: España Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Compuestos Organoplatinos / Profármacos / Antineoplásicos Límite: Animals / Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2024 Tipo del documento: Article País de afiliación: España Pais de publicación: Estados Unidos