Drug reservoir mechanism of Pt(II)-sulfur chelates based on pharmacokinetics of Pt(II) complex with thiols & thio-ethers: An experimental and theoretical approach

Synthesise of four different Pt(II) based complexes and investigate their experimental and DFT computational studies to understand the association rate of glutathione and dl-methionine for development of new anti-cancer drugs. [Display omitted] •Four Pt(II) based complexes with (N,N) bidentate, thiol and thio-ether chelating ligand have been synthesised and characterised by spectroscopic methods as model anticancer agent.•Pharmacokinetic study of Pt(II)-diaqua complex with Glutathione and dl-methionine bio-relevant molecules have been investigated.•Pt(II)-sulfur ‘drug reservoir’ mechanism of biomolecules with Pt(II)-diaqua complex have been proposed.•DFT calculation has been performed to measure HOMO-LUMO energy differences as well as different reactivity parameters and NBO analysis for the studied complexes.•TD-DFT simulated spectra of all the complexes support the experimental UV–Vis spectroscopy. Dichloro Pt(II) complex, Cis-[Pt(AEP)Cl2], C-1 was synthesized with bidentate chelating ligand 1-(2-Aminoethyl)-pyrrolidine (AEP) and hydrolyzed to the corresponding complex [Pt(AEP)(OH2)2](ClO4)2, C-2 to investigate their pharmacokinetics and theoretical study. Bio-relevant tri-peptide glutathione (GSH) and amino acid dl-methionine (dl-meth) substituted complex [Pt(AEP)(GSH)] C-3 and [Pt(AEP)(dl-meth)]2+C-4 were synthesized and characterized as model sulfur chelated anticancer agent. To observe the role of steric and electronic effect of the ligand in pharmacokinetics, at pseudo-first-order reaction condition and at pH 4.0, in vitro reactions of complex C-2 with GSH and dl-meth for bio-transformation to C-3 &C-4 respectively, were studied. To evaluate the mechanistic pathway of ‘drug reservoir’ activity. Two-step rate constants (k1 and k2) and activation parameters were assessed, which reflect the high and negative value of entropy of activation (ΔSǂ) and low and positive value of enthalpy of activation (ΔHǂ) to support an associative mechanism. A theoretical investigation was executed, which mainly emphasized on structural optimization, HOMO-LUMO energy, TD-DFT, IR simulations and reactivity parameters to observe a detailed insight into the electronic structure and bonding mode as well as bonding parameters of the complexes. Bonding mode of thiol and thio-ether in C-3 and C-4 were established with FT-IR spectroscopy and NBO analysis with all possible chelation in the substituted complexes which clearly reveals to the formation of C-3 and C-4 through (S, O), r