School of Chemical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
School of Biological Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
Inorg Chem. 2021 Feb 15;60(4):2414-2424. doi: 10.1021/acs.inorgchem.0c03317. Epub 2021 Jan 26.
The development of bifunctional platinum complexes with the ability to interact with DNA different binding modes is of interest in anticancer metallodrug research. Therefore, we report platinum(II) terpyridine complexes to target DNA by coordination and/or through a tethered alkylating moiety. The platinum complexes were evaluated for their antiproliferative properties against the human cancer cell lines HCT116 (colorectal), SW480 (colon), NCI-H460 (non-small cell lung), and SiHa (cervix) and generally exhibited potent antiproliferative activity although lower than their respective terpyridine ligands. H NMR spectroscopy and/or ESI-MS studies on the aqueous stability and reactivity with various small biomolecules, acting as protein and DNA model compounds, were used to establish potential modes of action for these complexes. These investigations indicated rapid binding of complex to the biomolecules through coordination to the Pt center, while in addition alkylated 9-ethylguanine. was investigated for its reactivity to the model protein hen egg white lysozyme (HEWL) by protein crystallography which allowed identification of the N atom of His15 as the binding site.
具有与 DNA 不同结合模式相互作用能力的双功能铂配合物的发展是抗癌金属药物研究中的一个关注点。因此，我们报告了铂(II)三联吡啶配合物通过配位和/或通过连接的烷化部分来靶向 DNA。评估了这些铂配合物对人癌细胞系 HCT116（结肠直肠）、SW480（结肠）、NCI-H460（非小细胞肺癌）和 SiHa（宫颈）的增殖活性，尽管它们的活性低于各自的三联吡啶配体，但通常表现出很强的增殖活性。通过对水稳定性和与各种小分子（作为蛋白质和 DNA 模型化合物）的反应性的 1H NMR 光谱和/或 ESI-MS 研究，建立了这些配合物的潜在作用模式。这些研究表明，复合物 1 通过与 Pt 中心配位迅速与生物分子结合，而 2 还烷基化了 9-乙基鸟嘌呤。通过蛋白质晶体学研究了 2 对模型蛋白鸡卵清溶菌酶 (HEWL) 的反应性，这使得可以确定 His15 的 N 原子为结合位点。
