Synthesis, structural characterisation and biological studies of new mononuclearplatinum(II) complexes with sterically hindered heterocyclic ligands

Three novel cisplatin analogues were synthesized, designed according to an approach which violatesthe ‘‘classical’’ structure–activity relationship, by replacing the diamine ligands with a planar N donorheterocycle giving a sterically hindered complex. Moreover, the sterical hindrance of antitumor drugcandidates potentially makes them less susceptible to deactivation by sulphur-containing proteinsand helping to overcome resistance mechanisms. The resulting mononuclear complexes of stericallyhindered polidentate heterocyclic N ligands [PtCl(bbp)]Cl (1) [bbp = 2,6-bis(2-benzimidazolyl)pyridine],[PtCl2(dptdn)](H2O) (2) [dptdn = sodium 5,6-diphenyl-3-(20-pyridyl)-1,2,4-triazine-400,400 0-disulfonate]and [(dptdn)(dpt)Pt]Cl2(H2O) (3) [dpt = 5,6-diphenyl-3-(20-pyridyl)-1,2,4-triazine] have been preparedand structurally characterised. Both neutral and ionic complexes are present, with monofunctional(1) and bifunctional Pt(II) moieties (2) and coordinatively saturated Pt(II) ions in the mixed ligand complex(3), whose size and shape enable them to behave as novel scaffolds for DNA binding. All complexeswere tested ‘‘in vitro’’ for their biological activity on human HT29 colorectal carcinoma and HepG2 hepatomacells. The complexes (1) and (3), endowed with a positive charge, showed a potent cytotoxicactivity and reduced cell viability with an efficacy higher than that of cisplatin; whilst the neutralbifunctional compound (2) was inactive. IC50 values have been calculated for the active compounds.The cytotoxic effects were confirmed by the accumulation of treated cells in subG0/G1 phase of cellcycle, by the loss of mitochondrial potential (Dwm) and by the chromatin condensation or fragmentationobserved by means of fluorescence microscopy after Hoechst 33258 nuclear staining. A study onintracellular platinum uptake in HT29 cell line has been also performed and data obtained stronglysuggest that the cytotoxicity of new tested complexes reported in this work is based on a differentpharmacodynamic pattern with respect to cisplatin.