Synthesis, Subcellular Localization and Anticancer Mechanism Studies of Unsymmetrical Iridium(III) Complexes

Two novel unsymmetrical Ir(III) complexes [Ir(ppy)₂(N N)Cl₂] (N N=2-(pyrazin-2-yl)naphtha[1,2-e][1,2,4]triazine, Ir1; 2-(pyrazin-2-yl)-4b,4b’-dihydroaceanthryleno[1,2-e][1,2,4]triazine, Ir2) were developed as chemotherapy agents. Ir1 was mainly located in mitochondria. In contrast, Ir2 accumulated in mitochondria but subsequently migrated to the nucleus. Ir1 and Ir2 showed cytotoxicity toward cancerous cells, especially the cisplatin-resistant ones, indicating their ability to overcome cisplatin resistance. Although both Ir1 and Ir2 disrupted mitochondrial metabolism, they showed different cell death mechanisms. Ir1 induced mitochondria-mediated apoptosis in cisplatin-resistant A549R cells. Ir2 was demonstrated to cause PARP-1 activated necroptosis in A549R cells. This study provides an experimental basis for the rational design of metal-based chemotherapeutic drugs.