Bioactivity, molecular docking and anticancer behavior of pyrrolidine based Pt(II) complexes: Their kinetics, DNA and...

The complex [Pt(AEP)Cl₂]; C-1 (where, AEP = 1-(2-Aminoethyl) pyrrolidine) and its hydrolyzed diaqua form cis-[Pt(AEP)(H₂O)₂]²⁺; C-2 were synthesized for their bioactivity and in vitro kinetic study with bioactive thiol group (-SH) containing ligands (like; L- cysteine and N-ac-L- cysteine) for their biological importance for 'drug reservoir' activity. The Thermal Gravimetric Analysis (TGA) was executed to confirm about the weight loss due to coordinated water molecules at high temperature range. At pH 4.0, the substitution behavior of C-2 with the thiols was studied in pseudo-first order reaction condition. The interaction mechanism of thiols with complex C-2 to their corresponding thiol substituted C-3 [Pt(AEP)(L-cys)] and C-4 [Pt(AEP)(N-ac-L-cys)] (where L-cys = L-cysteine and N-ac-L-cys = N-ac-L- cysteine) were proposed from their thermodynamical activation parameters (ΔH^≠ and ΔS^≠), which were obtained from Eyring equation. DNA and BSA binding activity of the complexes C-1 to C-4 were investigated by gel electrophoresis technique, spectroscopic titration and viscosity methods. The binding activity of the complexes with DNA and BSA was evaluated using a theoretical approach molecular docking study. The drug-like nature of the complexes is supported by the prediction of activity spectra for substance (PASS) from 2D structure of the Pt(II) complexes. Structural optimization, HOMO-LUMO energy calculation, Molecular electrostatic potential surface, NBO and TD-DFT calculation were executed by using density functional theory (DFT) with Gaussian 09 software package to pre-assessment of biological activity of the complexes. DFT-based descriptors were determined from the HOMO-LUMA energy to be related with the ability of binding affinity of Pt(II) complexes towards DNA and BSA to the formation of their corresponding adducts. The anticancer property of the design complexes were examined on HCT116 (colorectal carcinoma) cancer cell lines and as well as human normal cell NKE (Normal Kidney Epithelial) and compared with the recognised anticancer drug cisplatin. The Reactive Oxygen Species (ROS) production was assessed by DCFDA assay in presence of the Pt(II) complexes.