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
Group of Chemical and Environmental Engineering, Rey Juan Carlos University. C/Tulipán s/n, Móstoles, Madrid28933, Spain.
Department of Basic Health Sciences. Rey Juan Carlos University. Avda. Atenas s/n, Alcorcón, Madrid 28922, Spain.
J Med Chem. 2024 Apr 25;67(8):6410-6424. doi: 10.1021/acs.jmedchem.3c02393. Epub 2024 Apr 9.
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.
我们报道了两种新型的前药铂（IV）配合物，其轴向位置带有双有机硅烷配体：-二氯（二胺）--[3-（三乙氧基甲硅烷基）丙基氨基甲酸酯]铂（IV）（Pt（IV）-biSi-1）和-二氯（二异丙胺）--[3-（三乙氧基甲硅烷基）丙基氨基甲酸酯]铂（IV）（Pt（IV）-biSi-2）。与顺铂和Pt（IV）-biSi-1相比，Pt（IV）-biSi-2对结肠癌细胞（HCT 116和HT-29）表现出增强的细胞毒性。值得注意的是，Pt（IV）-biSi-2对癌细胞具有更高的细胞毒性，而对非致瘤性肠细胞（HIEC6）的毒性较低。在结直肠癌的临床前小鼠模型中，Pt（IV）-biSi-2在较低浓度下比顺铂更能有效抑制肿瘤生长，且副作用减少。从机制上讲，Pt（IV）-biSi-2诱导永久性DNA损伤，与p53水平无关。与顺铂的短暂作用相反，用Pt（IV）-biSi-2处理后，由组蛋白gH2Ax标记的双链断裂等DNA损伤是永久性的。Pt（IV）-biSi-2在接触生物还原剂后更快地还原为Pt（II）物种，这支持了其优越的生物学反应。这些发现揭示了一种设计具有增强活性和特异性的铂（IV）抗癌前药的新策略，为传统铂类药物之外的治疗提供了机会。
