Sartaj Tabassum

Synthesis, characterization and interaction studies of copper based drug with Human Serum Albumin (HSA): spectroscopic and molecular docking investigations.

A new water soluble copper(II) complex, [Cu(glygly)(ssz)(H(2)O)]⋅6H(2)O, 1 derived from dipeptide (glycyl glycine anion) and sulfasalazine was synthesized and characterized by elemental analysis (CHN), molar conductance measurements and spectroscopic methods (IR, UV-vis, ESI-MS). The complex 1 is non-ionic in nature and possess octahedral geometry around Cu(II) metal ion. The interaction of complex 1 with Human Serum Albumin (HSA) was investigated under physiological condition in Tris-HCl buffer solution at pH 7.4 by means of various spectroscopic methods (fluorescence, CD and FTIR) and molecular docking technique. The results of fluorescence titration revealed that the complex 1 strongly quench the intrinsic fluorescence of HSA through a static quenching procedure. Binding constants (K(b)) and the number of binding sites (n≈1) were calculated using modified Stern-Volmer equations. The thermodynamic parameters ΔG at different temperatures were calculated subsequently the value of ΔH and ΔS was also calculated which revealed that the hydrophobic and hydrogen bonding interactions play a major role in HSA-complex 1 association. The distance r between donor (HSA) and acceptor (complex 1) was obtained according to fluorescence resonance energy transfer and the alterations of HSA secondary structure induced by complex 1 were confirmed by FT-IR and CD measurements.

Interaction and photo-induced cleavage studies of a copper based chemotherapeutic drug with human serum albumin: spectroscopic and molecular docking study

The interaction of new dinuclear copper(ii) complex 1; [Cu(2)(glygly)(2)(ppz)(H(2)O)(4)]·2H(2)O, derived from dipeptide (glycyl glycine) and piperazine as a metallopeptide drug with human serum albumin (HSA) was examined by means of fluorescence spectroscopy which revealed that complex 1 has a strong ability to quench the intrinsic fluorescence of HSA through a static quenching procedure. The alterations of HSA secondary structure in the presence of complex 1 were confirmed by UV-visible, FT-IR, CD and 3D fluorescence spectroscopy. The binding constants (K), and binding site number (n), corresponding thermodynamic parameters ΔG, ΔH and ΔS at different temperatures were calculated. The molecular docking technique was utilized to ascertain the mechanism and mode of action towards the molecular target HSA indicating that complex 1 was located at the entrance of site I by electrostatic and hydrophobic forces, consistent with the corresponding experimental results. Complex 1 shows efficient photo-induced HSA cleavage activity, indicating the involvement of hydroxyl radicals as the reactive species. Furthermore, the cytotoxicity of 1 was examined on a panel of human tumor cell lines of different histological origins showing significant GI(50) values specifically towards MIAPACA2, A498 and A549 tumor cell lines. These results complement previous biological studies of new specific target metallopeptides, providing additional information about possibilities of their transport and disposition in blood plasma.

Synthesis and characterization of copper(II) and zinc(II)-based potential chemotherapeutic compounds: their biological evaluation viz. DNA binding profile, cleavage and antimicrobial activity.

Metal-based cancer chemotherapeutic agents of the type [Cu(phen)TzCl(2)]H(2)O 1 and [Zn(phen)(Tz)Cl(2)·H(2)O] 2, where phen = 1,10-phenanthroline and Tz = 1,2,4-triazole have been synthesized and characterized by various spectroscopic and analytical techniques. The structure of complex 1 was also determined by X-ray crystallography. The in vitro DNA binding studies of complexes 1 and 2 with CT DNA were carried out by various biophysical and molecular docking techniques. Both the complexes cleave supercoiled pBR322 DNA via hydrolytic pathway, as validated by T4 DNA ligase assay. Furthermore, both complexes exhibited significant antimicrobial activity. The results revealed that complex 1 has better prospectus to act as cancer chemotherapeutic candidate which warrants further in vitro and in vivo anticancer investigations.

Mixed-ligand Cu(II)–vanillin Schiff base complexes; effect of coligands on their DNA binding, DNA cleavage, SOD mimetic and anticancer activity

SOD mimics with varying coligand are momentous in developing potential chemotherapeutic drugs. Cu(II) based SOD mimics 1-4 [CuLH(OAc)(H(2)O)Y)] (LH = 2-((E)-(1,3-dihydroxy-2-methylpropan-2-ylimino)methyl)-6-methoxyphenol, OAc = CH(3)COO, 1: Y = H(2)O; 2: Y = phen (1,10-phenanthroline), 3: Y = tpimH (2,4,5-triphenylimidazole); 4: Y = tfbimH (2-(trifluoromethyl)benzimidazole) were synthesized and thoroughly characterized. Their interaction with CT-DNA showed different non-covalent binding behaviour. SOD activity of 2 was highest among 1-4 which was further validated by gel electrophoresis. The pBR322 plasmid strand break offered by 2 + O₂·⁻ system reveals oxidative cleavage mechanism. In vitro antimicrobial activity of 1-4 was shown by percent inhibition data while in vitro anticancer activity of 1-4 was screened using 16 human carcinoma cell lines of different histological origin. Complex 2 showed higher efficacy towards 14 cell lines.

Synthesis of new piperazine derived Cu(II)/Zn(II) metal complexes, their DNA binding studies, electrochemistry and anti-microbial activity : Validation for specific recognition of Zn(II) complex to DNA helix by interaction with thymine base

New 3,4:9,10-dibenzo-2,11-dihydroxy-1,12-bispiperazine-5,8-dioxododecane complexes [C(24)H(36)N(4)O(6)Cu] (1), [C(24)H(32)N(4)O(4)Zn] (2) have been synthesized and characterized by elemental analysis, IR, NMR, Mass, EPR, UV-vis spectroscopy and molar conductance measurements. The complexes are non-ionic in nature and possess octahedral geometry around Cu(2+), Zn(2+) central metal ions. The binding studies of 1 and 2 with calf thymus DNA (CT-DNA) were investigated by UV-vis, fluorescence, cyclic voltammetery and viscosity measurements. The calculated binding constant K(b) for 1 and 2 obtained from UV-vis absorption studies was 7.6x10(3)M(-1), 80.8x10(4)M(-1), respectively. The intrinsic binding constants were also estimated to be 7.0x10(4)M(-1) and 7.53x10(5)M(-1) for 1 and 2, respectively by using emission titrations. These experimental results suggest that complexes are groove binders and interact to CT-DNA with different affinities. Both the complexes in presence and absence of CT-DNA show quasireversible wave corresponding to Cu(II)/Cu(I) and Zn(II)/Zn(I) redox couple. The changes in E(1/2), DeltaE, I(pa)/I(pc) ascertain the interaction of 1 and 2 with CT-DNA. Further, decrease in viscosity of CT-DNA with increasing concentration of complexes was observed. In vitro, antimicrobial activity against fungi A. brassicicola, A. niger and bacteria E. coli, P. aeruginosa of complexes were carried out, which indicate that complex 2 is more active against both fungal and bacterial strains as shown by % inhibition data.

Template synthesis of novel carboxamide dinuclear copper (II) complex: spectral characterization and reactivity towards calf-thymus DNA

Dinuclear complexes Bis [aqua 1,8-(1,2-dicarboxamido benzene) 3,6-diazaoctane copper (II)/nickel (II)] tetrachloride (1 and 2) were synthesized by a two component one-pot metal template condensation between phthalic anhydride and 1,8-diamino 3,6-diazaoctane. Elemental analysis, molar conductance measurements, electronic absorption, infra-red, electron paramagnetic resonance, nuclear magnetic resonance, atomic absorption, and electron spray mass spectral studies have been performed to probe the nature and structure of the complexes. The interaction of copper (II) complex with calf thymus (CT-DNA) has been studied by using absorption, emission and circular dichoric spectral methods, viscometry, and cyclic voltammetry. A strong hyperchromism along with a red shift in UV bands and hypochromism in the ligand field band of the complex 1 on interaction with CT-DNA imply a covalent mode of DNA binding. This is further confirmed by studying the reactivity of complex 1 using circular dichroism and viscosity measurements. The variation in relative emission intensity of DNA-bound ethidium bromide observed upon treatment with the complex 1 parallel the trend of DNA binding studies. Cyclic voltammetry studies reveal that the complex 1 prefers to bind to DNA in Cu(II) rather than Cu(I) oxidation state.

Identification of a Potent Inhibitor of Human Dual-Specific Phosphatase, VHR, from Computer-Aided and NMR-Based Screening to Cellular Effects

Human vaccinia H1‐related phosphatase (VHR) is a dual‐specific phosphatase (DSPs) that plays an important role in the mitogen‐activated protein (MAP) kinase cascade regulation. It is also a potential drug target for diseases that are related to immune response. By combining a virtual and NMR‐based ligand‐screening strategy, we successfully identified four VHR inhibitors, of which GATPT ((glucosamine‐aminoethoxy)triphenyltin) can bind to VHR with a Ki value of 2.54 μM. The putative binding mode of GATPT was constructed by a molecular docking simulation to provide structural insights into the ligand‐binding mechanism. Furthermore, we found that this compound can significantly inhibit the dephosphorylation of the extracellular regulated kinases (ERKs), and c‐Jun N‐terminal kinases (JNKs) and block the G1–S phase transition in the cell cycle. Therefore, GATPT is a promising lead structure for designing more effective inhibitors of VHR.

Synthesis and structure elucidation of a copper(II) Schiff-base complex: In vitro DNA binding, pBR322 plasmid cleavage and HSA binding studies

New copper(II) complex with Schiff base ligand 4-[(2-Hydroxy-3-methoxy-benzylidene)-amino]-benzoic acid (H₂L) was synthesized and characterized by spectroscopic and analytical and single crystal X-ray diffraction studies which revealed that the complex 1 exist in a distorted octahedral environment. In vitro CT-DNA binding studies were performed by employing different biophysical technique which indicated that the 1 strongly binds to DNA in comparison to ligand via electrostatic binding mode. Complex 1 cleaves pBR322 DNA via hydrolytic pathway and recognizes minor groove of DNA double helix. The HSA binding results showed that ligand and complex 1 has ability to quench the fluorescence emission intensity of Trp 214 residue available in the subdomain IIA of HSA.

Nuclear blebbing of biologically active organoselenium compound towards human cervical cancer cell (HeLa): in vitro DNA/HSA binding, cleavage and cell imaging studies.

New pharmacophore organoselenium compound (1) was designed, synthesized and characterized by various spectroscopic methods (IR, ESI-MS, (1)H, (13)C and (77)Se NMR) and further confirmed by X-ray crystallography. Compound 1 consists of two 3,5-bis(trifluoromethyl)phenyl units which are connected to the selenium atom via the organometallic C-Se bond. In vitro DNA binding studies of 1 was investigated by absorption and emission titration methods which revealed that 1 recognizes the minor groove of DNA in accordance with molecular docking studies with the DNA duplex. Gel electrophoretic assay demonstrates the ability of 1 to cleave pBR322 DNA through hydrolytic process which was further validated by T4 religation assay. To understand the drug-protein interaction of which ultimate molecular target was DNA, the affinity of 1 towards HSA was also investigated by the spectroscopic and molecular modeling techniques which showed hydrophobic interaction in the subdomain IIA of HSA. Furthermore, the intracellular localization of 1 was evidenced by cell imaging studies using HeLa cells.

Synthesis and characterization of Cu(II)-based anticancer chemotherapeutic agent targeting topoisomerase Iα: in vitro DNA binding, pBR322 cleavage, molecular docking studies and cytotoxicity against human cancer cell lines.

New metal-based anticancer chemotherapeutic drug candidates [Cu(phen)L](NO₃)₂ (1) and [Zn(phen)L](NO₃)₂ (2) were synthesized from ligand L (derived from pharmacophore scaffold barbituric acid and pyrazole). In vitro DNA binding studies of the L, 1 and 2 were carried out by various biophysical techniques revealing electrostatic mode. Complex 1 cleaves pBR322 DNA via oxidative pathway and recognizes major groove of DNA double helix. The molecular docking study was carried out to ascertain the mode of action towards the molecular target DNA and enzymes. The complex 1 exhibited remarkably good anticancer activity on a panel of human cancer cell lines (GI₅₀ values < 10 μg/ml), and to elucidate the mechanism of cancer inhibition, Topo-I enzymatic activity was carried out.