Cytotoxic, DNA binding and drug reservoir property of Pt(II)–sulfur complexes: In-vitro kinetics, mechanism with bio-relevant molecules in aqueous medium and a theoretical approach

Abstract

Synthesis and cytotoxic property of Pt(II)–sulfur complexes are significant in biological aspect. In order to investigate their relevance, two sulfur chelated model complexes are considered for detailed study. In-vitro drug reservoir property of the complex [Pt(MAMP)(H2O)2]X22 (where, MAMP=2-[(N-methylamino)methyl]pyridine and X=NO3− or ClO4−) in model reactions with sulfur containing bio-molecules dl-methionine (dl-meth) and dl-penicillamine (dl-pen) are studied to explore the ‘drug reservoir’ mechanism. The complex [Pt(MAMP)(dl-meth)] 3 and [Pt(MAMP)(dl-pen)] 4 are synthesized from complex 2, which is obtained from the hydrolysis of complex [Pt(MAMP)Cl2] 1 and characterized by spectroscopic methods. Interaction mechanism between complex 2 with dl-meth and dl-pen has been established by kinetic study. Two step consecutive reaction rate constants (k1 and k2) and corresponding activation parameters (ΔH‡ and ΔS‡) for both the steps are calculated and an associative mechanism is proposed. Theoretical investigations like structural optimization, HOMO–LUMO energy calculations, NBO analysis have been performed. The coordination mode of dl-meth and dl-pen via (S, O) are established by spectroscopic methods and confirmed by NBO analysis. DNA binding property of the complexes 2–4 has been investigated by UV–Vis spectra, competitive binding experiment, gel electrophoresis and their corresponding binding constants (kb and ksv) are calculated. The computational molecular docking study is carried out for the complexes with B-DNA to confirm their DNA binding mode. Cytotoxic property of the complexes 3 and 4 are investigated on HeLa and HepG2 cell lines and also been compared with complex 2 and well known anticancer drug cisplatin and their corresponding IC50 values are calculated.