Seven membered chelate Pt(ii) complexes with 2,3-di(2-pyridyl)quinoxaline ligands: studies of substitution kinetics by sulfur donor nucleophiles, interactions with CT-DNA, BSA and in vitro cytotoxicity activities

摘要

Dichloro platinum(ii) complexes coordinated with 2,3-di(2-pyridyl)quinoxaline ligands which form seven-membered chelates namely, bpqPtCl(2), dmbpqPtCl(2) and bbqPtCl(2) (where bpq, dmbpq and bbq are 2,3-di(2-pyridyl)quinoxaline, 6,7-dimethyl-2,3-di(2-pyridyl)quinoxaline and 2,3-bis(2 ' pyriyl)benzo[g]quinoxaline, respectively) were synthesized, characterised and their respective hydrated product complexes namely, bpqPt(OH2)(2)(2+), dmbpqPt(OH2)(2)(2+) and bbqPt(OH2)(2)(2+) were prepared by chloride metathesis. The substitution kinetics of the aquated cations by thiourea nucleophiles indicated that the two aqua ligands are substituted simultaneously according to the rate law: k(obs) = k(2)[Nu]. This is followed by a forced dechelation of the ligands from the Pt (II) to form Pt(Nu)(4)(2+) species. The dechelation step is considerably slow to be monitored reliably. The rate of substitution is marginally enhanced by introducing two methyl groups and by extending the pi-conjugation on the bpq core ligand. The reactivity order increased as bpqPt(OH2)(2)(2+) < dmbpqPt(OH2)(2)(2+) < bbqPt(OH2)(2)(2+). Reactivity trends were well supported by theoretical computed DFT electronic descriptors. The interactions of the Pt(ii) complexes with CT-DNA and BSA were also examined spectroscopically in tris buffers at pH 7.2. Spectroscopic and viscosity measurements suggested strong associative interactions between the Pt(ii) complexes and CT-DNA, most likely through groove binding. In silico theoretical binding studies showed energetically stable poses through associative non-covalent interactions. In vitro MTT cytotoxicity IC50 values of the Pt(ii) complexes on human liver carcinoma cells (HepG2) cancer cell lines revealed bbqPtCl(2) as the least active. The fluorescence staining assays revealed the morphological changes suggested early apoptotic induction as well as non-specific necrosis.