Adjusting the DNA Interaction and Anticancer Activity of Pt(II) N‑Heterocyclic Carbene Complexes by Steric Shielding of the Trans Leaving Group

Five platinum­(II) complexes bearing
a (1,3-dibenzyl)­imidazol-2-ylidene
ligand but different leaving groups trans to it were examined for
cytotoxicity, DNA and cell cycle interference, vascular disrupting
properties, and nephrotoxicity. The cytotoxicity of complexes 3a–c increased with the steric shielding
of their leaving chloride ligand, and complex 3c, featuring
two triphenylphosphanes, was the most efficacious, with submicromolar
IC50 concentrations. Complexes 3a–c interacted with DNA in electrophoretic mobility shift and
ethidium bromide binding assays. The cationic complex 3c did not bind coordinatively to DNA but led to its aggregation, damage
that is not amenable to the usual repair mechanisms. Accordingly,
it arrested the cell cycle of melanoma cells in G1 phase, whereas cis-dichlorido­[(1,3-dibenzyl)­imidazol-2-ylidene]­(dimethyl
sulfoxide) platinum­(II) 3a induced G2/M phase arrest.
Complex 3c also disrupted the blood vessels in the chorioallantoic
membrane of fertilized chicken eggs. Ex vivo studies
using precision-cut tissue slices suggested the nephrotoxicities of 3a–c to be clinically manageable.