Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and, Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu, 273165, China.
Chembiochem. 2019 Nov 4;20(21):2767-2776. doi: 10.1002/cbic.201900268. Epub 2019 Oct 8.
Iridium(III) complexes have attracted more and more attention in the past few years because of their potential antineoplastic activity. In this study, four Ir complexes of the types [(η -Cp )Ir(N^N)Cl]PF (complexes 1 and 2) and [Ir(Phpy) (N^N)]PF (complexes 3 and 4) have been synthesized and characterized. They exhibit potential antineoplastic activity towards A549 cells, especially in the case of complex 1 [IC =(3.56±0.5) μm], which was nearly six times as effective as cisplatin [(21.31±1.7) μm]. Additionally, these complexes show some selectivity towards cancer cells over normal cells. They could be transported by serum albumin (binding constants were changed from 0.37×10 to 81.71×10 m ). Ir complexes 1 and 2 could catalyze the transformation of nicotinamide adenine dinucleotide reduced form (NADH) into NAD (turnover numbers 43.2, 11.9] and induce the accumulation of reactive oxygen species, thus confirming their antineoplastic mechanism of oxidation, whereas the cyclometalated complexes 3 and 4 were able to target the lysosome [Pearson co-localization coefficient (PCC)=0.73], cause lysosomal damage, and induce apoptosis. Understanding the mechanism of action would help further structure-activity optimization on these Ir complexes as emerging cancer therapeutics.
在过去的几年中，由于其潜在的抗肿瘤活性，铱（III）配合物引起了越来越多的关注。在这项研究中，合成并表征了四种类型的[（η-Cp）Ir（N^N）Cl]PF（配合物 1 和 2）和[Ir（Phpy）（N^N）]PF（配合物 3 和 4）的 Ir 配合物。它们对 A549 细胞表现出潜在的抗肿瘤活性，尤其是配合物 1 [IC=（3.56±0.5）μm]，其效果几乎是顺铂的六倍[（21.31±1.7）μm]。此外，这些配合物对癌细胞相对于正常细胞具有一定的选择性。它们可以被血清白蛋白转运（结合常数从 0.37×10 变为 81.71×10 m）。Ir 配合物 1 和 2 可以催化烟酰胺腺嘌呤二核苷酸还原形式（NADH）转化为 NAD（周转率分别为 43.2、11.9）并诱导活性氧物质的积累，从而证实了它们的氧化抗肿瘤机制，而环金属化配合物 3 和 4 能够靶向溶酶体[皮尔逊共定位系数（PCC）=0.73]，导致溶酶体损伤并诱导细胞凋亡。了解作用机制将有助于进一步对这些作为新兴癌症治疗剂的 Ir 配合物进行结构-活性优化。
