Derivation of Structure–Activity Relationships from the Anticancer Properties of Ruthenium(II) Arene Complexes with 2-Aryldiazole Ligands

Abstract

The ligands 2-pyridin-2-yl-1H-benzimidazole (HL(1)), 1-methyl-2-pyridin-2-ylbenzimidazole (HL(2)), and 2-(1H-imidazol-2-yl)pyridine (HL(3)) and the proligand 2-phenyl-1H-benzimidazole (HL(4)) have been used to prepare five different types of new ruthenium(II) arene compounds: (i) monocationic complexes with the general formula [(η(6)-arene)RuCl(κ(2)-N,N-HL)]Y [HL = HL(1), HL(2), or HL(3); Y = Cl or BF4; arene = 2-phenoxyethanol (phoxet), benzene (bz), or p-cymene (p-cym)]; (ii) dicationic aqua complexes of the formula [(η(6)-arene)Ru(OH2)(κ(2)-N,N-HL(1))](Y)2 (Y = Cl or TfO; arene = phoxet, bz, or p-cym); (iii) the nucleobase derivative [(η(6)-arene)Ru(9-MeG)(κ(2)-N,N-HL(1))](PF6)2 (9-MeG = 9-methylguanine); (iv) neutral complexes consistent with the formulation [(η(6)-arene)RuCl(κ(2)-N,N-L(1))] (arene = bz or p-cym); (v) the neutral cyclometalated complex [(η(6)-p-cym)RuCl(κ(2)-N,C-L(4))]. The cytototoxic activity of the new ruthenium(II) arene compounds has been evaluated in several cell lines (MCR-5, MCF-7, A2780, and A2780cis) in order to establish structure-activity relationships. Three of the compounds with the general formula [(η(6)-arene)RuCl(κ(2)-N,N-HL(1))]Cl differing in the arene moiety have been studied in depth in terms of thermodynamic dissociation constants, aquation kinetic constants, and DNA binding measurements. The biologically most active compound is the p-cym derivative, which strongly destabilizes the DNA double helix, whereas those with bz and phoxet have only a small effect on the stability of the DNA double helix. Moreover, the inhibitory activity of several compounds toward CDK1 has also been evaluated. The DNA binding ability of some of the studied compounds and their CDK1 inhibitory effect suggest a multitarget mechanism for their biological activity.

Alteration of steric hindrance modulates glutathione resistance and cytotoxicity of three structurally related RuII-p-cymene complexes

“…The similarity in the DNA binding constants for the 12 h hydrolyzed sample and the fresh solution of complexes may be attributed to the slow hydrolysis, since the timescale of the DNA binding experiment is smaller (1.5 h). The p-cymene complexes of Ru II show similar binding constants with DNA as reported by Garcia et al [47][48][49][50] Aquation is thought to be a major step which may be involved in activation of this type of metal complex. However, extracellular aquation may prevent the internalization of the complexes due to their di-positive charge and higher hydrophilicity.…”

Monomer–Dimer Divergent Behavior toward DNA in a Half-Sandwich Ruthenium(II) Aqua Complex. Antiproliferative Biphasic Activity

“…2 X-ray Diffraction. The crystal structures of the dicationic complex [(η 6 -p-cymene)Ru(OH 2 )(κ 2 -N,N-HL 1 )](OTf) 2 , [2c]-(OTf) 2 ·H 2 O, and the monocationic derivative [(η 6 -p-cymene)-Ru(OH 2 )(κ 2 -N,N-L 1 )](BF 4 ), [2c′](BF 4 ), have been elucidated for the first time by X-ray diffraction.…”

“…All non-hydrogen atoms were refined with anisotropic displacement coefficients, except those included in the model of disorder for the trifluoromethanesulfonate anions. All hydrogen atoms were added to their geometrically ideal positions except those corresponding to the water molecules and N3 of [2c](OTf) 2 Additional X-ray tables, Ang's method calculations, and T-jump biexponential curves are available free of charge via the Internet at http://pubs.acs.org.…”

Influence of Halogen Substitution in the Ligand Sphere on the Antitumor and Antibacterial Activity of Half-sandwich Ruthenium(II) Complexes [RuX(η6 -arene)(C5 H4 N-2-CH=N-Ar)]+

“…Cancer refers to a range of diseases characterized by the uncontrollable proliferation of abnormal cells that invade and disrupt tissues . The treatment of cancer is accomplished by a number of therapies such as chemotherapy, radiation therapy, immunotherapy, monoclonal antibody therapy, or surgery .…”