Anticancer activity of heteroleptic diimine complexes of dirhodium: A study of intercalating properties, hydrophobicity and in cellulo activity

Abstract

The series of complexes cis-[Rh(2)(mu-O(2)CCH(3))(2)(dppn)(L)](2+), where dppn = benzo[i]dipyrido[3,2-a:2',3'-c] phenazine, and L = bpy (2,2'-bipyridine) (1), phen (1,10-phenanthroline) (2), dpq (dipyrido[3,2-f:2',3'-h]quinoxaline) (3), dppz (dipyrido[3,2-a:2',3'-c]phenazine) (4), and dppn (5) were synthesized and their effect on the human cancer cells HeLa and COLO-316 was monitored. Complexes 1 and 2 interact with DNA through intercalation, whereas compounds 3-5 bind only electrostatically. It was found that the dirhodium complex 4 is the most effective compound at inhibiting cell viability of the human cancer cells HeLa and COLO-316. A general conclusion is that the hydrophobicity of the compounds correlates with their in cellulo activity in both cell lines. The ability of the compounds to reach nuclear DNA and form adducts was explored using the comet assay. The results indicate that compounds 1-5 either do not form adducts with DNA that are detrimental to the cell or that they are successfully repaired by the cellular machinery. The results of an annexin V assay indicate that compounds 1-4 trigger apoptosis, whereas compound 5 clearly does not. These findings are significant because they support the contention that dirhodium complexes can be tuned to direct their effect to cellular targets other than nuclear DNA.

Control and utilization of ruthenium and rhodium metal complex excited states for photoactivated cancer therapy

“…The cis -[Rh 2 ( μ -O 2 CCH 3 ) 2 (dppn)(NN)] 2+ (NN = bpy, phen, dpq, dppz, and dppn) complexes exhibit dark toxicity toward HeLa and COLO-316 cancer cell lines, with the bpy, phen, dpq, and dppz complexes transversing the cellular membrane to induce apoptosis, while the dppn complex is unable to enter the cell and induces necrosis [65]. The cytotoxicity studies of this series toward Hs-27 fibroblasts shows that the dppz and dppn complexes are less cytotoxic in the dark than the bpy, phen, and dpq complexes, with LC 50 values of 200 ± 20, 178 ± 17, 51 ± 5, 355 ± 18, and 384 ± 24 μM (LC 50 = median lethal concentration) for NN = bpy, phen, dpq, dppz, and dppn, respectively [64].…”

Confocal Fluorescence Microscopy Studies of a Fluorophore-Labeled Dirhodium Compound: Visualizing Metal–Metal Bonded Molecules in Lung Cancer (A549) Cells

“…10 The most active complex, [Rh 2 (μ-O 2 CCH 3 ) 2 (η 1 -O 2 CCH 3 )(dppz)(CH 3 OH) 3 ] + ( 2 ; dppz = dipyrido[3,2- a :2′,3′- c ]phenazine, Figure S1), is able to induce DNA strand breaks in cellulo at concentrations similar to that of cisplatin. A closely related compound with two NˆN ligands, namely [Rh 2 (μ-O 2 CCH 3 ) 2 (dppn)(dppz)(CH 3 OH) 2 ] 2+ ( 3 ; dppn = benzo[ i ]dipyrido[3,2- a :2,3- c ]phenazine, Figure S1), was found to be active against the same cancer cell lines, 11 but it does not induce DNA damage at its cytotoxic concentration, supporting the contention that other mechanisms of action are switched on simply by changing the ligand environment around the dimetal unit. 11 …”

“…A closely related compound with two NˆN ligands, namely [Rh 2 (μ-O 2 CCH 3 ) 2 (dppn)(dppz)(CH 3 OH) 2 ] 2+ ( 3 ; dppn = benzo[ i ]dipyrido[3,2- a :2,3- c ]phenazine, Figure S1), was found to be active against the same cancer cell lines, 11 but it does not induce DNA damage at its cytotoxic concentration, supporting the contention that other mechanisms of action are switched on simply by changing the ligand environment around the dimetal unit. 11 …”

To intercalate or semiintercalate, or both?

“…This interaction may be stabilized by hydrogen bonding from the diimine ligands that is not present in the bis-phen compounds. The inhibition of transcription in vitro observed for dirhodium complexes possessing polypyridyl ligands may also require reinvestigation, because semi- COMMENTARY intercalation is also possible in these systems (10,11). In contrast to the bending of the double helix associated with inhibition of transcription, undisrupted nucleobase π-stacking interactions are required for longrange charge transport (CT) mediated by DNA (2).…”