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

摘要

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