Half-Sandwich Iridium(III) and Ruthenium(II) Complexes Containing P^P-Chelating Ligands: A New Class of Potent Anticancer Agents with Unusual Redox Features

Abstract

A series of half-sandwich Ir pentamethylcyclopentadienyl and Ru arene complexes containing P^P-chelating ligands of the type [(Cp/arene)M(P^P)Cl]PF, where M = Ir, Cp is pentamethylcyclopentadienyl (Cp*), or 1-biphenyl-2,3,4,5-tetramethyl cyclopentadienyl (Cp); M = Ru, arene is 3-phenylpropan-1-ol (bz-PA), 4-phenylbutan-1-ol (bz-BA), or p-cymene (p-cym), and P^P is 2,20-bis(diphenylphosphino)-1,10-binaphthyl (BINAP), have been synthesized and fully characterized, three of them by X-ray crystallography, and their potential as anticancer agents explored. All five complexes showed potent anticancer activity toward HeLa and A549 cancer cells. The introduction of a biphenyl substituent on the Cp* ring for the iridium complexes has no effect on the antiproliferative potency. Ruthenium complex [(η-p-cym)Ru(P^P)Cl]PF (5) displayed the highest potency, about 15 and 7.5 times more active than the clinically used cisplatin against A549 and HeLa cells, respectively. No binding to 9-MeA and 9-EtG nucleobases was observed. Although these types of complexes interact with ctDNA, DNA appears not to be the major target. Compared to iridium complex [(η-Cp*)Ir(P^P)Cl]PF (1), ruthenium complex (5) showed stronger ability to interfere with coenzyme NAD/NADH couple through transfer hydrogenation reactions and to induce ROS in cells, which is consistent with their anticancer activities. The redox properties of the complexes 1, 5, and ligand BINAP were evaluated by cyclic voltammetry. Complexes 1 and 5 arrest cell cycles at the S phase, Sub-G phase and G phase, respectively, and cause cell apoptosis toward A549 cells.

Organometallic ruthenium and iridium phosphorus complexes: Synthesis, cellular imaging, organelle targeting and anticancer applications

“…However, the anticancer activity of complex Ru1 containing the P^P‐chelating ligand L1 is lower than that of Ir1 and Ir4 containing L1, probably due to the hydrophilicity of −OH causing difficulties in entering the cell membrane . A similar result has also appeared in our previous reports . Ru3 containing L4 is 2 × more active than Ru2 containing L2 against HeLa human cervical cancer cells, suggesting that the introduction of a benzene ring on the ligand L2 can increase the anticancer activity of the complexes to some extent.…”

“…Ru3 containing L4 is 2 × more active than Ru2 containing L2 against HeLa human cervical cancer cells, suggesting that the introduction of a benzene ring on the ligand L2 can increase the anticancer activity of the complexes to some extent. When more benzene rings are added to the ligand L4 to form ligand BINAP, the anticancer activity of the corresponding η 6 ‐ p ‐cym ruthenium complex is further increased (IC 50 from 5.6 to 1.4 μ m ) . Another striking result is that the biphenyl complex Ir4 displayed lower IC 50 values than the structurally similar Cp* derivative Ir1 , and similar rules have been reported by Aird et al The results clearly indicate that subtle structural changes can have a significant impact on the antiproliferative activity.…”

“…Compared with complexes contain the P^P‐chelating ligand BINAP, the distance between the centroid of η 5 ‐Cp* or η 6 ‐ p ‐cym and the metal center (1.8824 Å, 1.7616 Å, respectively) in Ir3 and Ru3 are shorter, due to the comparatively weak trans effect of the ligands in Ir3 and Ru3 . It has been reported that the steric hindrance around the metal center was reflected by the bite angle in Cp*(P–P)MX .…”

“…All the complexes were synthesized using an analogical procedure according to the reported method (Scheme ) . All the complexes were characterized through 1 H‐NMR spectra, elemental analyses (C, H and P) and mass spectroscopy (MS).…”

Dual Functional Half‐Sandwich Ru(II) Complexes: Lysosome‐Targeting Probes and Anticancer Agents

“…However, similar to other cytotoxic drugs, problems of platinum‐based anticancer drugs, normal tissue toxicity, and drug resistance limit their future use . These factors necessitate the exploration of new chemotype anticancer agents that have metal and new mechanisms of action different from platinum …”