Couples of N-heterocyclic
carbene complexes of
ruthenium,
iridium,
platinum, and
gold, each differing only in the
carbene ligand being either 1,3-dimethylimidazol-2-ylidene (IM) or 1,3-dimethyl-N-boc-O-methylhistidin-2-ylidene (HIS), were assessed for their antiproliferative effect on seven
cancer cell lines, their interaction with
DNA, their cell cycle interference, and their vascular disrupting properties. In MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide] assays only the
platinum complexes were cytotoxic at single-digit micromolar IC50 concentrations with the (HIS)Pt complex being on average twice as active as the (IM)Pt complex. The former was highly efficacious against
cisplatin-resistant HT-29 colon
carcinoma cells where the latter had no effect. Both Pt complexes were accumulated by
cancer cells and bound to double-helical
DNA equally well. Only the (HIS)Pt complex modified the electrophoretic mobility of
circular DNA in vitro due to the HIS
ligand causing greater morphological changes to the
DNA. Both
platinum complexes induced accumulation of 518A2
melanoma cells in G2/M and S phase of the cell cycle. A disruption of blood vessels in the chorioallantoic membrane of fertilized chicken eggs was observed for both
platinum complexes and the (IM)
gold complex. The (HIS)
platinum complex was as active as
cisplatin in
tumor xenografted mice while being tolerated better. We found that the HIS
ligand may augment the cytotoxicity of certain antitumoral
metal fragments in two ways: by acting as a transmembrane carrier increasing the cellular accumulation of the complex, and by initiating a pronounced distortion and unwinding of
DNA. We identified a new (HIS)
platinum complex which was highly cytotoxic against
cancer cells including
cisplatin-resistant ones.