Photoactivatable, mitochondria targeting dppz iridium(III) complex selectively interacts and damages mitochondrial DNA in cancer cells

Chem Biol Interact. 2024 Feb 19:110921. doi: 10.1016/j.cbi.2024.110921. Online ahead of print.ABSTRACTCyclometalated Ir(III) complex [Ir(L)2 (dppz)]PF6 (where L = 1-methyl-2-(thiophen-2-yl)-1H-benzo [d]imidazole and dppz = dipyrido [3,2-a:2',3'-c]phenazine) (Ir1) is potent anticancer agent whose potency can be significantly increased by irradiation with blue light. Structural features of the cyclometalated Ir(III) complex Ir1 investigated in this work, particularly the presence of dppz ligand possessing an extended planar area, suggest that this complex could interact with DNA. Here, we have shown that Ir1 accumulates predominantly in mitochondria of cancer cells where effectively and selectively binds mitochondrial (mt) DNA. Additionally, the results demonstrated that Ir1 effectively suppresses transcription of mitochondria-encoded genes, especially after irradiation, which may further affect mitochondrial (and thus also cellular) functions. The observation that Ir1 binds selectively to mtDNA implies that the mechanism of its biological activity in cancer cells may also be connected with its interaction and damage to mtDNA. Further investigations revealed that Ir1 tightly binds DNA in a cell-free environment, with sequence preference for GC over AT base pairs. Although the dppz ligand itself or as a ligand in structurally similar DNA-intercalating Ru polypyridine complexes based on dppz ligand intercalates into DNA, the DNA binding mode of Ir1 comprises surprisingly a groove...
Source: Chemico-Biological Interactions - Category: Molecular Biology Authors: Source Type: research