Study on the Multimodal Anticancer Mechanism of Ru(II)/Ir(III) Complexes Bearing a Poly(ADP-ribose) Polymerase 1 Inhibitor
- J Med Chem. 2023 Oct 12;66(19):13731-13745. doi: 10.1021/acs.jmedchem.3c01156.
- 1. Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China.
- 2. School of Chemistry and Life Sciences, Suzhou University of Science and Technology, Suzhou 215009, China.
- 3. Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China.
A series of novel ruthenium(II) and iridium(III) complexes (Ru1-Ru3 and Ir1-Ir3) with different ancillary ligands and a PARP-1-inhibitory chelating ligand 2-(2,3-dibromo-4,5-dimethoxybenzylidene)hydrazine-1-carbothioamide (L1) were designed and prepared. The target complexes were structurally characterized by NMR and ESI-MS techniques. Among them, the crystal and molecular structures of Ir1 and Ir2 were also determined by X-ray crystallography. These complexes retained the PARP-1 enzyme inhibitory effect of L1 and showed potent antiproliferative activity on the tested Cancer cell lines. The ruthenium(II) complexes Ru1-Ru3 were found to be more cytotoxic than the iridium(III) complexes Ir1-Ir3. Further investigations revealed that the most active complex Ru3 induced Apoptosis in MCF-7 cells by multiple modes, inclusive of inducing DNA damage, suppressing DNA damage repair, disturbing cell cycle distribution, decreasing the mitochondrial membrane potential, and increasing the intracellular Reactive Oxygen Species levels.