Universidad de Castilla-La Mancha, Departamento de Química Inorgánica, Orgánica y Bioquímica, Facultad de Ciencias y Tecnologías Químicas, IRICA, Avda. C. J. Cela, 10, 13071 Ciudad Real, Spain.
Universidad de Castilla-La Mancha, Departamento de Química Física, Facultad de Ciencias y Tecnologías Químicas, Avda. C. J. Cela s/n, 13071 Ciudad Real, Spain.
J Inorg Biochem. 2021 May;218:111403. doi: 10.1016/j.jinorgbio.2021.111403. Epub 2021 Mar 9.
The problems of resistance and side effects associated with cisplatin and other chemotherapeutic drugs have boosted research aimed at finding new compounds with improved properties. The use of platinum(IV) prodrugs is one alternative, although there is some controversy regarding the predictive ability of the peak reduction potentials. In the work described here a series of fourteen chloride Pt(II) and Pt(IV) compounds was synthesised and fully characterised. The compounds contain different bidentate arylazole heterocyclic ligands. Their cytotoxic properties against human lung carcinoma (A549), human breast carcinoma (MCF7) and human colon carcinoma (HCT116 and HT29) cell lines were studied. A clear relationship between the type of ligand and the anti-proliferative properties was found, with the best results obtained for the Pt(II) compound that contains an aniline fragment, (13), thus evidencing a positive effect of the NH group. Stability and aquation studies in DMSO, DMF and DMSO/water mixtures were carried out on the active complexes and an in-depth analysis of the two aquation processes, including DFT analysis, of 13 was undertaken. It was verified that DNA was the target and that cell death occurred by apoptosis in the case of 13. Furthermore, the cytotoxic derivatives did not exhibit haemolytic activity. The reduction of the Pt(IV) compounds whose Pt(II) congeners were active was studied by several techniques. It was concluded that the peak reduction potential was not useful to predict the ability for reduction. However, a correlation between the cytotoxic activity and the standard reduction potential was found.
与顺铂和其他化疗药物相关的耐药性和副作用问题促使人们加大力度研究，以寻找具有改良性能的新化合物。铂（IV）前药的应用是一种替代方法，尽管有关峰还原电位的预测能力存在一些争议。在本文所描述的工作中，合成并充分表征了十四种氯化铂（II）和铂（IV）化合物。这些化合物含有不同的双齿芳基唑杂环配体。研究了它们对人肺癌（A549）、人乳腺癌（MCF7）和人结肠癌细胞（HCT116 和 HT29）系的细胞毒性。发现配体的类型与抗增殖特性之间存在明显的关系，含有苯胺片段的 Pt(II)化合物（13）的效果最好，这表明 NH 基团具有积极的影响。在 DMSO、DMF 和 DMSO/水混合物中对活性配合物进行了稳定性和水合研究，并对 13 的两个水合过程进行了深入的分析，包括 DFT 分析。结果证实 DNA 是靶标，在 13 的情况下，细胞死亡是通过细胞凋亡发生的。此外，细胞毒性衍生物没有表现出溶血活性。通过几种技术研究了铂（IV）化合物的还原，这些铂（IV）化合物的 Pt(II)同系物具有活性。研究结果表明，峰还原电位对于预测还原能力没有用处。然而，发现细胞毒性活性与标准还原电位之间存在相关性。
