Sankar Ch. Moi

Ligand substitution reaction on a platinum(II) complex with bio-relevant thiols: kinetics, mechanism and bioactivity in aqueous medium

The kinetics of the interaction between [Pt(pic)(H2O)2](ClO4)2, cis-diaqua(2-aminomethylpyridine)platinum(II) perchlorate 1 and selected thiols (L-cysteine and N-acetyl-L-cysteine) has been studied spectrophotometrically in aqueous medium as a function of complex and thiol concentrations, pH, and temperature at constant ionic strength. The observed pseudo-first-order rate constants kobs (s−1) obeyed the equation kobs = k1[thiol]. At pH = 4.0, complex 1 interacts with the thiols via two distinct consecutive steps. The first step is dependent while the second step is independent of ligand concentration. The rate constants for the process are of the order: k1 ≈ 10−3 M−1 s−1 and k2 ≈ 10−5 s−1. The association equilibrium constant (KE) for the outer sphere complex formation has been evaluated together with the rate constants for the two subsequent steps. Both the steps are ligand-assisted anation and the final step is the ring closure process. The activation parameters for both steps were evaluated using Eyrings equation. The low ΔH‡1 = (34.91 ± 0.97 kJ mol−1) and ΔH‡2 = (29.10 ± 0.72 kJ mol−1) values and large negative values of ΔS‡1 = (−174.68 ± 2.18 J K−1 mol−1) and ΔS‡2 = (−233.74 ± 2.4 J K−1 mol−1) for both the anation steps were evaluated. On the basis of the kinetic observations, evaluated activation parameters and spectroscopic data, a plausible associative mechanism is proposed for both processes. Antibacterial properties on both gram positive and gram negative bacteria and anticancer properties of complex 1 and its substituted complexes 2 and 3 on HeLa cells have been investigated. Complexes 1 to 3 show remarkable growth inhibition of bacteria. They also show anticancer activity of about 70% when compared to cis-platin. The complexes bind to DNA and change its electrophoretic mobilization pattern in agarose gel.

In vitro model reaction of sulfur containing bio-relevant ligands with Pt( ii ) complex: kinetics, mechanism, bioactivity and computational studies

cis-[Pt(MAMP)Cl2] 1 and its hydrolysed product cis-[Pt(MAMP)(H2O)2]2+ 2 (where MAMP = 2-[(N-methylamino)methyl]pyridine) were synthesised and characterised by spectroscopic methods. Kinetic and mechanistic studies were followed on complex 2 with thiols; L-cysteine (L-cys) and N-acetyl-L-cysteine (N-ac-L-cys). The thiol substituted products [Pt(MAMP)(L-cys)] 3 and [Pt(MAMP)(N-ac-L-cys)] 4 formation mechanisms were proposed and characterized. Their bonding modes were also confirmed spectroscopically and theoretically. At pH 4.0, the interactions of complex 2 with the ligands show two distinct consecutive steps: the first step is dependent and the second is independent of [ligand]. The association equilibrium constant (KE) for the outer sphere complex formation and rate constants for both steps have been evaluated. The activation parameters (ΔH‡ and ΔS‡) for both the steps were calculated using the Eyring equation and an associative mechanism is proposed for both the reactions. Structural optimization, HOMO–LUMO energy calculation, and Natural Bond Orbital (NBO) analysis of complexes 2–4 were investigated with Density Functional Theory (DFT). The complexes bind strongly to DNA and change its electrophoretic mobilization pattern in agarose gel. For theoretical understanding of the binding interaction of complex 2 with B-DNA, a molecular docking study was performed. Anticancer properties of all the three complexes 2–4 were probed on both HeLa and Hep G2 cell lines which shows remarkable activity of 70–75% compared to cisplatin at 50.0 μM concentration. Significant growth inhibition by the complexes in both Gram positive and Gram negative bacteria was observed. The water soluble complexes 2–4 may be further investigated and might be considered as chemotherapeutic agents.

Interaction of bio-relevant thio-ether and thiols with dinuclear Pd(II) complex: kinetics, mechanism, bioactivity in aqueous medium and molecular docking

The kinetics of interaction between [Pd(pic)(OH)]2(ClO4)2, 2 (pic = 2-aminomethylpyridine) with the selected ligands (L) DL-methionine (DL-meth), L-cysteine (L-cys) and N-acetyl-L-cysteine (N-ac-L-cys) have been studied under pseudo-first order conditions using a stopped-flow spectrophotometer in aqueous medium as a function of [complex 2] as well as [ligand], pH, and temperature at constant ionic strength. The ligand dependent second order reaction is found to take place in two consecutive steps in accordance with the rate law, k(obs) = k1[L]2 in which all these three reactions follow the third order kinetics. The first step of the reaction is dependent, while the second step is independent of [ligand] in all the cases. The activation parameters, ΔH‡ and ΔS‡ for the two-step reactions are evaluated from the Eyring equation. An associative mode of activation (an associative mechanism) in the transition state is proposed for all these substitution processes. Complex 2 and its substituted products [Pd(pic)DL-meth]+ 3; [Pd(pic)L-cys] 4; and [Pd(pic)N-ac-L-cys] 5 are characterized by UV-Vis, FT-IR, 1H-NMR and ESI-mass spectroscopic methods. Complex 2–5 show remarkable anticancer properties on HeLa cells of about 70% at high concentration when compared to cis-platin and antibacterial properties on both the Gram positive (Bacillus subtilis) and Gram negative (E. coli Dh5α) bacteria. In addition, DNA interaction with plasmid DNA is observed and computational molecular docking studies were carried out with an aim to establish the binding mode of complex 2 with B-DNA.

Benzimidazole based Pt(II) complexes with better normal cell viability than cisplatin: synthesis, substitution behavior, cytotoxicity, DNA binding and DFT study

cis-[Pt(ambim)Cl2] 1 (where, ambim = 2-aminomethylbenzimidazole) has been synthesized and characterized by spectroscopic methods. Reaction kinetics between the hydrolyzed product, cis-[Pt(ambim)(H2O)2]2+2 with DL-penicillamine (DL-pen) and glutathione (GSH) have been studied spectrophotometrically in aqueous medium. At pH 4.0, the interactions of 2 with the ligands show two distinct consecutive steps. The association equilibrium constant (KE) for the outer sphere complex formation and rate constants for both the steps have been evaluated. Activation parameters (ΔH‡ and ΔS‡) were evaluated using the Eyring equation and an associative mechanism is proposed for both the reactions. Computational studies using Density Functional Theory (DFT) were carried out to investigate the electronic structures of the complexes. To study the nature of the electronic transitions in complex 1, time dependent DFT was performed. The DNA binding properties of the complexes 2–4 were evaluated by spectroscopic titration, fluorescence indicator displacement experiments and electrophoresis measurements. The complexes effectively bind to calf-thymus DNA via different binding modes with intrinsic binding constants (Kb) in the range of 2.22 × 104 to 4.76 × 104 M−1 which was supported by molecular docking studies. The antiproliferative properties of 2–4 were probed in vitro against human cervical cancer, non-small cell lung carcinoma and hepatocellular liver carcinoma cell lines and 2 was found to be most effective in growth inhibition in all the cell lines. Remarkably, the complexes also generate lower levels of reactive oxygen species (ROS) than cisplatin and have almost no adverse effects on normal cells.

An experimental and theoretical approach on the kinetics and mechanism for the formation of a four-membered (S, S) chelated Pt(II) complex

The interaction of a chemoprotective agent, diethyldithiocarbamate (DDTC), with cis-[Pt(pic)(H2O)2]2+, 2 (where pic = 2-aminomethylpyridine), in aqueous medium was investigated experimentally and theoretically. The equilibrium constant (KE) for the formation of the outer sphere association complex and the rate constants for both steps have been evaluated experimentally, and were compared with the theoretically determined values. The activation parameters (ΔHǂ, ΔSǂ and ΔGǂ) for both the steps were calculated and an associative mechanism is proposed. The bonding modes of the product [Pt(pic)(DDTC)]+, 3, were confirmed by spectroscopic measurements and supported by Time Dependent Density Functional Theory (TD-DFT) and Natural Bond Orbital (NBO) calculations. Penta coordinated platinum transition state geometries for both the steps were fully optimized and confirmed by frequency analysis and an intrinsic reaction coordinate method molecular docking study has been performed to understand the binding interaction of complex 2 with B-DNA. The anticancer properties of 2 and 3 were investigated on a HeLa cell line, and they showed remarkable activity of about 70% compared to cisplatin at 50 μM concentration.

Kinetics and mechanism of biphasic substitution reactions of a platinum(II) complex with thioglycollic acid and 4-methyl-3-thiosemicarbazide in aqueous solution

The kinetics of interactions between cis-diaqua(2-aminomethylpyridine)platinum(II) perchlorate (1) [Pt(pic)(OH2)2](ClO4)2, thioglycollic acid (TGA), and 4-methyl-3-thiosemicarbazide (MTSC) have been studied spectrophotometrically in aqueous medium as a function of the [complex (1)] as well as [TGA] or [MTSC], pH and temperature at constant ionic strength. The observed pseudo-first-order rate constants were proportional to [TGA] or [MTSC]. At pH 4.0, the interactions of (1) with both TGA and MTSC show two distinct consecutive steps; the first step is dependent and second independent of [TGA] or [MTSC]. The association equilibrium constant (KE) for the outer sphere complex formation has been evaluated, along with the rate constants for the two steps. The first step is assigned to ligand-assisted anation and the second to chelation of TGA or MTSC. The activation parameters for both the steps were evaluated using Eyring’s equation. On the basis of the kinetic observations and evaluated activation parameters, an associative mechanism is proposed for both the reactions.

Synthesis, biological evaluation, substitution behaviour and DFT study of Pd(II) complexes incorporating benzimidazole derivative

To achieve potent yet specific antitum agents, a series of palladium(II) complexes (C1–C6) employing the carrier ligand 2-aminomethylbenzimidazole with DNA intercalating property and diverse ancillary groups (chloride, aqua, thiol) were synthesized and characterized. The kinetic parameters of the reactivity of the diaqua complex C2 towards selected sulphur-containing biomolecules were evaluated under pseudo-first order reaction conditions. Theoretical calculations such as NBO and TD-DFT were found to corroborate with spectroscopic results. Intercalative/groove binding nature of calf-thymus DNA (CT-DNA) interaction for the complexes was confirmed by various physico-chemical techniques and molecular docking. A strong association of the complexes with bovine serum albumin (BSA) via a static mechanism was demonstrated by absorption and emission measurements. The anti-proliferative effects of the complexes were tested against human breast tumor MDA-MB-231, human lung carcinoma A549 and human hepatocellular liver carcinoma HepG2. The complexes exhibited inhibitory effects greater than that exhibited by recognized drug cisplatin on the MDA-MB-231 cell line. Notably, the growth inhibition as well as oxidative stress elicited by the complexes in non-malignant cell lines L6 myotubes (rat myoblasts) and HEK-293 (human embryonic kidney cells) was much less than by cisplatin.

Kinetics and mechanism of interaction of Pt(II) complex with bio-active ligands and in vitro Pt(II)-sulfur adduct formation in aqueous medium: bio-activity and computational study

Abstract Kinetics of interaction between [Pt(pic)(H2O)2](ClO4)2, 2 (where pic = 2-aminomethylpyridine) with the selected ligands DL-methionine (DL-meth) and DL-penicillamine (DL-pen) have been studied spectrophotometrically in aqueous medium separately as a function of [2] as well as [ligand], pH and temperature at constant ionic strength. The association equilibrium constants (KE) for the outer sphere complex formation have been evaluated together with the rate constants for the two subsequent steps. Activation parameters (enthalpy of activation ΔH≠ and entropy of activation ΔS≠) were calculated from the Eyring equation. An associative mechanism of substitution is proposed for both reactions on the basis of the kinetic observations, evaluated activation parameters, and spectroscopic data. Structural optimizations, HOMO-LUMO energy calculation, and Natural Bond Orbital (NBO) analysis of 2–4 were carried out with Density Functional Theory. Bonding mode of thiol and thio-ether is confirmed by spectroscopic analyses and NBO calculation. Cytotoxic properties of 2–4 were explored on A549 carcinoma cell lines; DNA-binding properties of the complexes were also investigated by gel electrophoresis.

A New Bis(aquated) High Relaxivity Mn(II) Complex as an Alternative to Gd(III)-Based MRI Contrast Agent

Disclosed here are a piperazine, a pyridine, and two carboxylate groups containing pentadentate ligand H2pmpa and its corresponding water-soluble Mn(II) complex (1). DFT-based structural optimization implied that the complex had pentagonal bipyramidal geometry where the axial positions were occupied by two water molecules, and the equatorial plane was constituted by the ligand ON3O donor set. Thus, a bis(aquated) disc-like Mn(II) complex has been synthesized. The complex showed higher stability compared with Mn(II)-EDTA complex [log KMnL = 14.29(3)] and showed a very high r1 relaxivity value of 5.88 mM-1 s-1 at 1.41 T, 25 °C, and pH = 7.4. The relaxivity value remained almost unaffected by the pH of the medium in the range of 6-10. Although the presence of 200 equiv of fluoride and bicarbonate anions did not affect the relaxivity value appreciably, an increase in the value was noticed in the presence of phosphate anion due to slow tumbling of the complex. Cell viability measurements, as well as phantom MR images using clinical MRI imager, consolidated the possible candidature of complex 1 as a positive contrast agent.