Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Mie 513-8670, Japan.
Faculty of Pharmaceutical Sciences, Osaka Medical and Pharmaceutical University, Osaka 569-1094, Japan.
Inorg Chem. 2022 Aug 8;61(31):12155-12164. doi: 10.1021/acs.inorgchem.2c01126. Epub 2022 Jul 25.
Tetrazolato-bridged dinuclear platinum(II) complexes ([{-Pt(NH)}(μ-OH)(μ-5-R-tetrazolato-,)]; tetrazolato-bridged complexes) show remarkable cytotoxic effects and antitumor activity . Here, we examined the structure-activity relationship of a series of fluorine-containing derivatives (R = CFH, CFH, or CF), focusing on their lipophilicity, cellular accumulation, cytotoxicity, interactions with a nucleobase and double-stranded deoxyribonucleic acid, and antitumor efficacy. Fluorination had a little effect on the properties of the derivatives ; however, marked differences in cytotoxicity and tumor growth inhibition activity were observed. In BALB/c mice bearing colon-26 tumors, the antitumor efficacies of the derivatives were markedly altered, even by changing the number of fluorine atoms by one. In addition, one derivative, {-Pt(NH)}(μ-OH)(μ-5-difluoromethyltetrazolato-,), showed a significantly higher antitumor efficacy compared with oxaliplatin, a current first-line drug and the only platinum-based drug approved for the treatment of colon cancer. Together, the present results indicate that introducing fluorine into tetrazolato-bridged complexes may be useful for modulating activities.
桥连四唑双核铂（II）配合物（[{-Pt(NH₃)}（μ-OH）（μ-5-R-四唑基-）]}；桥连四唑配合物）具有显著的细胞毒性和抗肿瘤活性。在这里，我们研究了一系列含氟衍生物（R = CFH、CF₃或 CF）的构效关系，重点研究了它们的亲脂性、细胞积累、细胞毒性、与碱基和双链脱氧核糖核酸的相互作用以及抗肿瘤功效。氟原子的取代对衍生物的性质影响不大，但观察到细胞毒性和肿瘤生长抑制活性有显著差异。在携带结肠-26 肿瘤的 BALB/c 小鼠中，即使通过一个氟原子的数量变化，衍生物的抗肿瘤功效也发生了明显改变。此外，一种衍生物[{-Pt(NH₃)}（μ-OH）（μ-5-二氟甲基四唑基-）]（NO）与当前的一线药物奥沙利铂（唯一一种批准用于治疗结肠癌的铂类药物）相比，显示出更高的抗肿瘤功效。总之，这些结果表明，在桥连四唑配合物中引入氟原子可能有助于调节活性。
