Designing specific inhibitors against dihydrofolate reductase of W. bancrofti towards drug discovery for lymphatic filariasis

Structural Chemistry - Lymphatic filariasis (LF) is one among the leading neglected diseases caused by mosquitoe-borne parasite Wuchereria bancrofti to humans. Though drugs are available for the...     

磁性纳米颗粒固定化细菌纤维素酶的活性和稳定性

在氨水溶液中进行Fe+2和Fe+3离子共沉淀并水热处理后制得磁性纳米颗粒Fe3O4,通过戊二醛活化将纤维素酶固定于其上。采用基于响应面法的Box-Behnken法(BBD)优化了制备条件,如磁性纳米颗粒浓度、戊二醛浓度、酶浓度和交联时间。 BBD分析结果表明,用实验数据可合理调节二次模型。利用生成的基于统计数据的等高线评价了响应面的变化,以理解纳米颗粒和酶活性之间的关系。运用扫描电镜、X射线衍射和红外光谱表征了纳米颗粒上酶的尺寸、结构、形貌和结合情况。采用诸如pH值、温度、重复使用性和存储能力分析了固定化纤维素酶的活性和稳定性。发现固定后的纤维素酶表现出更好的稳定性和活性。     

Spectral characteristics of desipramine in β-cyclodextrin cavity through inclusion complex

The inclusion complexation behavior and its characterization of Desipramine (DP) with β-Cyclodextrin (β-CD) in solution phase are analyzed by UV and fluorescence spectroscopy. The solid inclusion complex is characterized by FT-IR, SEM, Powder XRD and TG/DTA. The stoichiometric ratio of the complexation is found to be 1:1. The orientation and structure of the complex are proposed based on the analysis of Patch-Dock server. The formation of inclusion complex has been confirmed on the base of the changes of spectroscopic properties will be encapsulated in partly either by any aromatic ring or by the aliphatic side chain. But our results showed that the aliphatic group of DP is in the cavity of β-CD.β-CD encapsulation and enhances the in-vitro cytotoxicityeffect of DP compound by forming inclusion complex in the solid state.     

Synthesis,characterization and electrochemical behavior of mononuclear,binuclear nickel(II) and heterobinuclear zinc(II)nickel(II) complexes derived from novel macrobicyclic tricompartmental ligands: kinetics of the catalytic hydrolysis of 4-nitrophenyl phosphate by the complexes

Mononuclear, binuclear Ni^II and heterobinuclear Zn^IINi^II complexes have been derived from lateral macrobicyclic tricompartmental ligands embracing three different donor sets: (i) O₂N₂-donor set, derived from ether oxygens and tertiary amine nitrogens; (ii) N₂O₂-donor set, derived from tertiary amine nitrogens and phenolic oxygens; (iii) O₂N₂-donor set, derived from phenolic oxygens and azomethine nitrogens. Cyclic voltammograms of the mononuclear Ni^II complexes showed irreversible one-electron reduction processes in the –1.2 to –1.3 V region and an irreversible oxidation process in the range +0.8 V potential region. The binuclear complexes showed quasireversible two-step single electron reduction processes around the –1.3 and –1.7 V potential regions. The anodic potential region showed an irreversible oxidation process at +1.0 V. The heterobinuclear Zn^IINi^II complex showed an irreversible reduction of the Ni^II species at –1.55 V. The catalytic hydrolysis towards 4-nitrophenyl phosphate by the mononuclear, binuclear Ni^II complexes and the heterobinuclear complex were found to be appreciable. The pseudo-first order rate constant for the catalytic hydrolysis catalyzed by the binuclear and heterobinuclear complexes were found to be higher (9.8 × 10^–4 s^–1) than that of the corresponding mononuclear complexes (1.3 × 10^–5 s^–1), which ascertain the requirement of two metal ions in close proximity for the binding of the nucleophilic OH and the phosphate group.     

Molecular Dynamics Approach to Probe the Allosteric Inhibition of PTP1B by Chlorogenic and Cichoric Acid

Protein tyrosine phosphatase 1B (PTP1B), a major negative regulator of the insulin and leptin signaling pathway, is a potential target for therapeutic intervention against diabetes and obesity. The recent discovery of an allosteric site in PTP1B has created an alternate strategy in the development of PTP1B targeted therapy. The current study investigates the molecular interactions between the allosteric site of PTP1B with two caffeoyl derivatives, chlorogenic acid (CGA) and cichoric acid (CHA), using computational strategies. Molecular docking analysis with CGA and CHA at the allosteric site of PTP1B were performed and the resulting protein-ligand complexes used for molecular dynamics simulation studies for a time scale of 10 ns. Results show stable binding of CGA and CHA at the allosteric site of PTP1B. The flexibility of the WPD loop was observed to be constrained by CGA and CHA in the open (inactive), providing molecular mechanism of allosteric inhibition. The allosteric inhibition of CGA and CHA of PTP1B was shown to be favorable due to no restriction by the α-7 helix in the binding of CGA and CHA at the allosteric binding site. In conclusion, our results exhibit an inhibitory pattern of CGA and CHA against PTP1B through potent binding at the allosteric site.     

Stereoselective synthesis of piperidinone and quinolinone systems via ring opening reactions using TiCl4/silyl reagents

Titanium(IV) chloride and silyl reagents mediated regio- and chemoselective ring opening reactions of oxa-bridged piperidinone ring systems were demonstrated. This methodology interestingly undergoes the stereoselective ring opening at the C-O bond of oxa-bridged piperidinone ring systems. Study of TiCl₄ with hydride or non-hydride silyl reagents furnished the product with selectivity. This protocol is highly valuable to synthesize a range of stereoselective piperidinones, quinolinones ring systems.     

A series of oxyimine-based macrocyclic dinuclear zinc(II) complexes enhances phosphate ester hydrolysis, DNA binding, DNA hydrolysis, and lactate dehydrogenase inhibition and induces apoptosis

A symmetrical macrocyclic dizinc(II) complex (1) has been synthesized by using the ligand (L(1)) [μ-11,24-dimethyl-4,7,16,19-tetraoxa-3,8,15,20-tetraazatricyclo-[20.3.1.1(10,13)] heptacosa-1(25),2,7,9,11,13(27),14,20,22(26),23-decaene-26,27-diol]. A series of unsymmetrical macrocyclic dizinc(II) complexes (2-6) has been synthesized by Schiff base condensation of bicompartmental mononuclear complex [ZnL] [μ-3,16-dimethyl-8,11-dioxa-7,12-diazadicyclo-[1.1(14,18)] heptacosa-1,3,5(20),6,12,14,16,18(19)-octacaene-19,20-diolato)zinc(II)] with various diamines like 1,2-diamino ethane (L(2)), 1,3-diamino propane (L(3)), 1,4-diamino butane (L(4)), 1,2-diamino benzene (L(5)), and 1,8-diamino naphthalene (L(6)). The ligand L(1) and all the zinc(II) complexes were structurally characterized. To corroborate the consequence of the aromatic moiety in comparison to the aliphatic moiety present in the macrocyclic ring on the phosphate ester hydrolysis, DNA binding and cleavage properties have been studied. The observed first order rate constant values for the hydrolysis of 4-nitrophenyl phosphate ester reaction are in the range from 2.73 × 10(-2) to 9.86 × 10(-2) s(-1).The interactions of complexes 1-6 with calf thymus DNA were studied by spectroscopic techniques, including absorption, fluorescence, and circular dichroism spectroscopy. The DNA binding constant values of the complexes were found in the range from 1.80 × 10(5) to 9.50 × 10(5) M(-1), and the binding affinities are in the following order: 6 > 5 > 1 > 2 > 3 > 4. All the dizinc(II) complexes 1-6 effectively promoted the hydrolytic cleavage of plasmid pBR322 DNA under anaerobic and aerobic conditions. Kinetic data for DNA hydrolysis promoted by 6 under physiological conditions give the observed rate constant (k(obs)) of 4.42 ± 0.2 h(-1), which shows a 10(8)-fold rate acceleration over the uncatalyzed reaction of ds-DNA. The comparison of the dizinc(II) complexes 1-6 with the monozinc(II) complex [ZnL] indicates that the DNA cleavage acceleration promoted by 1-6 are due to the efficient cooperative catalysis of the two close proximate zinc(II) cation centers. The ligand L(1), dizinc(II) complexes 1, 3, and 6 showed cytotoxicity in human hepatoma HepG2 cancer cells, giving IC(50) values of 117, 37.1, 16.5, and 8.32 μM, respectively. The results demonstrated that 6, a dizinc(II) complex with potent antiproliferative activity, is able to induce caspase-dependent apoptosis in human cancer cells. Cytotoxicity of the complexes was further confirmed by the lactate dehydrogenase enzyme level in HepG2 cell lysate and content media.