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

Abstract

Dichloro platinum(II) complexes coordinated with 2,3-di(2-pyridyl)quinoxaline ligands which form seven-membered chelates namely, bpqPtCl₂, dmbpqPtCl₂ and bbqPtCl₂ (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)₂²⁺, dmbpqPt(OH₂)₂²⁺ and bbqPt(OH₂)₂²⁺ 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 = k₂[Nu]. This is followed by a forced dechelation of the ligands from the Pt (II) to form Pt(Nu)₄²⁺ 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 π-conjugation on the bpq core ligand. The reactivity order increased as bpqPt(OH₂)₂²⁺ < dmbpqPt(OH₂)₂²⁺ < bbqPt(OH₂)₂²⁺. 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 bbqPtCl₂ as the least active. The fluorescence staining assays revealed the morphological changes suggested early apoptotic induction as well as non-specific necrosis.