16-Electron Half-Sandwich Rhodium(III), Iridium(III), and Ruthenium(II) Complexes as Lysosome-Targeted Anticancer Agents

Abstract

The 18-electron half-sandwich platinum group (Rh, Ru, Ir, and Os) metal anticancer complexes have been largely reported due to their easy tunable structure, high potency toward cancer cells, and specific mechanism of actions. However, the 16electron (without the leaving group Cl − ) half-sandwich complexes and their biological evaluation are rarely investigated. With an easy access to the required α-keto-β-diimine ligands using m-CPBA as oxidant, we herein reported the synthesis and characterization of a panel of structurally related 16-electron piano-stool rhodium, iridium, and ruthenium complexes through the rearranged coordination reaction. These complexes have been well-established by NMR spectroscopy, mass spectrometry, single-crystal X-ray crystallography, and elemental analysis. Each of these complexes was stable and exhibited fluorescence in solution. Although no reaction with nucleobase (9-EtG and 9-MeA) was observed, the representative Rh5 showed affinity toward CT-DNA. These 16electron complexes showed promising activity toward A549 and HeLa cancer cells with the values of IC 50 in the range 7.1−32.3 μM, which was comparable to or even better than cisplatin. In addition, the structure−activity relationships were observed that the change of the metal center from iridium(III) and ruthenium(II) to rhodium(III) could enhance the cytotoxicity of these unsaturated complexes. The investigation of mechanism of actions (MoAs) using flow cytometry displayed that the cytotoxicity of the complex Rh5 was associated with the perturbation of the cell cycle and the induction of cell apoptosis. Moreover, microscopic analysis by confocal microscopy suggested that the representative 16-electron complex Rh5 entered A549 cells via energy-dependent pathway and predominantly accumulated in lysosomes, thus resulting in the disruption of lysosomal integrity.

Half-Sandwich Iridium(III), Rhodium(III), and Ruthenium(II) Complexes Chelating Hybrid sp2-N/sp3-N Donor Ligands to Achieve Improved Anticancer Selectivity

“…The chloro-bridged bimetallic Ir­(III), Rh­(III), and Ru­(II) precursors D1 – D8 were synthesized using the reported procedures. − Reactions of these precursors with the ligands L1 – L3 and NH 4 PF 6 in a mixture of dichloromethane and methanol for 5 h at an ambient temperature gave rise to the complexes Ir1 – Ir7 , Rh1 – Rh5 , and Ru1 – Ru4 in 41–59% isolated yields (Scheme ). All of these complexes were soluble in common solvents such as DMSO, dichloromethane, methanol, and acetonitrile and showed sufficient stability in air.…”

“…The absolute emission quantum yields of selected complexes Ir1 , Rh1 , and Ru1 are relatively low ( Ir1 : 0.39%, Rh1 : 0.31%, Ru1 : 0.15%) in methanol solutions. This weakly photoluminescent behavior was also observed in the previously reported half-sandwich Ir­(III), Rh­(III), and Ru­(II) complexes. ,, However, the photoluminescent characteristic of these complexes rendered it possible to explore MoAs by bioimaging.…”

“…The aryl-BIAN compound was prepared according to literature methods . The chloro-bridged bimetallic Ir­(III), Rh­(III), and Ru­(II) precursors D1 ([(η 5 -Cp*)­IrCl 2 ] 2 ), D2 ([(η 5 -Cp ph )­IrCl 2 ] 2 ), D3 ([(η 5 -Cp biph )­IrCl 2 ] 2 ), D4 ([(η 5 -Cp*)­RhCl 2 ] 2 ), D5 ([(η 5 -Cp ph )­RhCl 2 ] 2 ), D6 ([(η 5 -Cp cy )­RhCl 2 ] 2 ), D7 ([(η 6 -benzene)­RuCl 2 ] 2 ), and D8 ([(η 6 - p -cymene)­RuCl 2 ] 2 ) were synthesized using the reported procedures. − The 1 H, 13 C­{ 1 H} NMR spectroscopies were measured via Bruker DPX 500 spectrometers (Figures , , S1–S38, S58, S66–S68, S73–S75, S79, and S80). Absorption spectroscopy was determined by a TU-1901 UV–visible recording spectrophotometer.…”

“…This weakly photoluminescent behavior was also observed in the previously reported half-sandwich Ir(III), Rh(III), and Ru(II) complexes. 40,44,55 However, the photoluminescent characteristic of these complexes rendered it possible to explore MoAs by bioimaging.…”

Increasing Anticancer Activity with Phosphine Ligation in Zwitterionic Half-Sandwich Iridium(III), Rhodium(III), and Ruthenium(II) Complexes

“…The bimetallic iridium­(III), rhodium­(III), and ruthenium­(II) precursors [(η 5 -C 5 Me 5 )­MCl 2 ] 2 (M = Ir ( D1 ); Rh ( D5 )), [(η 5 -Cp R )­MCl 2 ] 2 (Cp R = C 5 (CH 3 ) 4 R, R = Cy (M = Ir ( D2 ); M = Rh ( D6 )), 2-methylbenzene (M = Ir ( D4 )), 3,5-bis­(trifluoromethyl)­benzene) (M = Ir ( D3 ); Rh ( D7 )) and [(η 6 -arene)­RuCl 2 ] 2 ( D8 – D10 ) were prepared by the reported methods ,,− or using the modified procedure ( D6 ; see the Supporting Information). It should be noted that the arene ligand of ruthenium complexes is different from that of iridium and rhodium complexes since the presence of η 6 -arene substituent was identified to stabilize ruthenium complexes in the +2 oxidation state by being relatively inert to displacement. − Moreover, another motivation for the development of air-stable η 6 -arene ruthenium­(II) complexes was the activation by reduction hypothesis, which suggested that active ruthenium­(II) species may be formed in vivo from ruthenium­(III) complexes. − Scheme shows the synthetic procedure of zwitterionic phosphine–imine half-sandwich iridium­(III), rhodium­(III), and ruthenium­(II) complexes containing sulfonate moiety.…”