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

The
ligands 2-pyridin-2-yl-1H-benzimidazole (HL1), 1-methyl-2-pyridin-2-ylbenzimidazole (HL2), and 2-(1H-imidazol-2-yl)­pyridine (HL3) and the proligand
2-phenyl-1H-benzimidazole (HL4) have been
used to prepare five different types of new ruthenium­(II) arene compounds:
(i) monocationic complexes with the general formula [(η6-arene)­RuCl­(κ2-N,N-HL)]Y [HL = HL1, HL2, or HL3; Y = Cl or BF4; arene = 2-phenoxyethanol (phoxet),
benzene (bz), or p-cymene (p-cym)];
(ii) dicationic aqua complexes of the formula [(η6-arene)­Ru­(OH2)­(κ2-N,N-HL1)]­(Y)2 (Y = Cl or TfO; arene
= phoxet, bz, or p-cym); (iii) the nucleobase derivative
[(η6-arene)­Ru­(9-MeG)­(κ2-N,N-HL1)]­(PF6)2 (9-MeG = 9-methylguanine); (iv) neutral complexes consistent
with the formulation [(η6-arene)­RuCl­(κ2-N,N-L1)] (arene
= bz or p-cym); (v) the neutral cyclometalated complex
[(η6-p-cym)­RuCl­(κ2-N,C-L4)]. 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 [(η6-arene)­RuCl­(κ2-N,N-HL1)]­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.