Base excision and nucleotide excision repair pathways in mycobacteria

About a third of the human population is estimated to be infected with Mycobacterium tuberculosis. The bacterium displays an excellent adaptability to survive within the host macrophages. As the reactive environment of macrophages is capable of inducing DNA damage, the ability of the pathogen to safeguard its DNA against the damage is of paramount significance for its survival within the host. Analysis of the genome sequence has provided important insights into the DNA repair machinery of the pathogen, and the studies on DNA repair in mycobacteria have gained momentum in the past few years. The studies have revealed considerable differences in the mycobacterial DNA repair machinery when compared with those of the other bacteria. This review article focuses especially on the aspects of base excision, and nucleotide excision repair pathways in mycobacteria. (C) 2011 Elsevier Ltd. All rights reserved.

Curcumin-glucoside, A Novel Synthetic Derivative of Curcumin, Inhibits alpha-Synuclein Oligomer Formation: Relevance to Parkinson's Disease

alpha-Synuclein aggregation is centrally implicated in Parkinson's disease (PD). It involves multi-step nucleated polymerization process via the formation of dimers, soluble toxic oligomers and insoluble fibrils. In the present study, we synthesized a novel compound viz., Curcumin-glucoside (Curc-gluc), a modified form of curcumin and studied its anti-aggregating potential with alpha-synuclein. Under aggregating conditions in vitro, Curc-gluc prevents oligomer formation as well as inhibits fibril formation indicating favorable stoichiometry for inhibition. The binding efficacies of Curc-gluc to both alpha-synuclein monomeric and oligomeric forms were characterized by micro-calorimetry. It was observed that titration of Curc-gluc with alpha-synuclein monomer yielded very low heat values with low binding while, in case of oligomers, Curc-gluc showed significant binding. Addition of Curc-gluc inhibited aggregation in a dose-dependent manner and enhanced alpha-synuclein solubility, which propose that Curc-gluc solubilizes the oligomeric form by disintegrating preformed fibrils and this is a novel observation. Overall, the data suggest that Curc-gluc binds to alpha-synuclein oligomeric form and prevents further fibrillization of alpha-synuclein; this might aid the development of disease modifying agents in preventing or treating PD.

Dithienylcyclopentadienone derivative-co-benzothiadiazole: An alternating copolymer for organic photovoltaics

Alternating copolymer of 7,9-di(thiophen-2-yl)-8H-cyclopenta[a]acenaphthylen-8-one-co-benzothia diazole was synthesized by palladium(0) catalyzed Stille coupling reaction. This solution processable copolymer shows an excellent thermal stability and has a broad absorption range from 300 to 800 nm with a band gap of about 1.51 eV. High LUMO energy level and low band gap of the synthesized copolymers suggest that, this copolymer will be a suitable donor material for use in an organic photovoltaic device. Photovoltaic devices were fabricated from the blend of copolymer and phenyl-C61-butyric acid methyl ester as the active material. (C) 2011 Elsevier By. All rights reserved.

Lewis Base Catalysis by Thiourea: N-Bromosuccinimide-Mediated Oxidation of Alcohols

In recent times, (thio)urea derivatives have become synonymous with hydrogen bonding owing to their extensive applicability as small molecule organocatalysts. In this paper, another activation mode by thiourea derivatives, namely via Lewis base catalysis, is disclosed for the NBS-mediated oxidation of alcohols. The mild reaction conditions employed here is suitable for chemoselective oxidation of secondary alcohol in the presence of primary alcohol.

Effect of base dissipation on the granular flow down an inclined plane

The effect of base dissipation on the granular flow down an inclined plane is examined by altering the coefficient of restitution between the moving and base particles in discrete element (DE) simulations. The interaction laws between two moving particles are kept fixed, and the coefficient of restitution (damping constant in the DE simulations) between the base and moving particles are altered to reduce dissipation, and inject energy from the base. The energy injection does result in an increase in the strain rate by up to an order of magnitude, and the temperature by up to two orders of magnitude at the base. However, the volume fraction, strain rate and temperature profiles in the bulk (above about 15 particle diameters from the base) are altered very little by the energy injection at the base. We also examine the variation of h(stop), the minimum height at the cessation of flow, with energy injection from the base. It is found that at a fixed angle of inclination, h(stop) decreases as the energy dissipation at the base decreases.

Cyclopentac]thiophene oligomers based solution processable D-A copolymers and their application as FET materials

Two new solution processable, low band gap donor-acceptor (D-A) copolymers (P1 and P2) comprising a cyclopentac] thiophene (CPT) based oligomers as donors and benzoc]1,2,5] selenadiazole (BDS) and 2-dodecyl1,2,3]-benzotriazole (BTAz) as acceptors were synthesized and characterized and their field effect transistor properties were studied. The internal charge transfer interaction between the electron-donating CPT based oligothiophene and the electron-accepting BDS or BTAz unit effectively reduces the band gap in polymers to 1.3 and 1.66 eV with low lying highest occupied molecular orbital (HOMO). The absorption spectrum of P1 was found to be more red shifted than that of P2 because of incorporation of the more electron-withdrawing BDS unit. The color of neutral P1 was found to be green in both solution and film states with two major bands in the absorption spectra; however, neutral P2 revealed one dominant absorption exhibiting red color in both solution and film state which could be attributed to the less electron-withdrawing effect of the BTAz unit. The polymers were further characterized by GPC, TGA, DSC and cyclic voltammetry. P1 and P2 exhibited charge carrier mobilities as high as 9 x 10(-3) cm(2) V-1 s(-1) and 2.56 x 10(-3) cm 2 V-1 s(-1), respectively with the current on/off ratio (I-on/I-off) in the order of 10(2).

Transition due to base roughness in a dense granular flow down an inclined plane

Particle simulations based on the discrete element method are used to examine the effect of base roughness on the granular flow down an inclined plane. The base is composed of a random configuration of fixed particles, and the base roughness is decreased by decreasing the ratio of diameters of the base and moving particles. A discontinuous transition from a disordered to an ordered flow state is observed when the ratio of diameters of base and moving particles is decreased below a critical value. The ordered flowing state consists of hexagonally close packed layers of particles sliding over each other. The ordered state is denser (higher volume fraction) and has a lower coordination number than the disordered state, and there are discontinuous changes in both the volume fraction and the coordination number at transition. The Bagnold law, which states that the stress is proportional to the square of the strain rate, is valid in both states. However, the Bagnold coefficients in the ordered flowing state are lower, by more than two orders of magnitude, in comparison to those of the disordered state. The critical ratio of base and moving particle diameters is independent of the angle of inclination, and varies very little when the height of the flowing layer is doubled from about 35 to about 70 particle diameters. While flow in the disordered state ceases when the angle of inclination decreases below 20 degrees, there is flow in the ordered state at lower angles of inclination upto 14 degrees. (C) 2012 American Institute of Physics. http://dx.doi.org/10.1063/1.4710543]

A Rhodanine Derivative CCR-11 Inhibits Bacterial Proliferation by Inhibiting the Assembly and GTPase Activity of FtsZ

A perturbation of FtsZ assembly dynamics has been shown to inhibit bacterial cytokinesis. In this study, the antibacterial activity of 151 rhodanine compounds was assayed using Bacillus subtilis cells. Of 151 compounds, eight strongly inhibited bacterial proliferation at 2 mu M. Subsequently, we used the elongation of B. subtilis cells as a secondary screen to identify potential FtsZ-targeted antibacterial agents. We found that three compounds significantly increased bacterial cell length. One of the three compounds, namely, CCR-11 (E)-2-thioxo-5-({3-(trifluoromethyl)phenyl]furan-2-yl}methylene) thiazolidin-4-one], inhibited the assembly and GTPase activity of FtsZ in vitro. CCR-11 bound to FtsZ with a dissociation constant of 1.5 +/- 0.3 mu M. A docking analysis indicated that CCR-11 may bind to FtsZ in a cavity adjacent to the T7 loop and that short halogen oxygen, H-bonding, and hydrophobic interactions might be important for the binding of CCR-11 with FtsZ. CCR-11 inhibited the proliferation of B. subtilis cells with a half-maximal inhibitory concentration (IC50) of 1.2 +/- 0.2 mu M and a minimal inhibitory concentration of 3 mu M. It also potently inhibited proliferation of Mycobacterium smegmatis cells. Further, CCR-11 perturbed Z-ring formation in B. subtilis cells; however, it neither visibly affected nucleoid segregation nor altered the membrane integrity of the cells. CCR-11 inhibited HeLa cell proliferation with an IC50 value of 18.1 +/- 0.2,mu M (similar to 15 x IC50 of B. subtilis cell proliferation). The results suggested that CCR-11 inhibits bacterial cytokinesis by inhibiting FtsZ assembly, and it can be used as a lead molecule to develop FtsZ-targeted antibacterial agents.

Novel Levamisole Derivative Induces Extrinsic Pathway of Apoptosis in Cancer Cells and Inhibits Tumor Progression in Mice

Background: Levamisole, an imidazo(2,1-b) thiazole derivative, has been reported to be a potential antitumor agent. In the present study, we have investigated the mechanism of action of one of the recently identified analogues, 4a (2-benzyl-6-(4'-fluorophenyl)-5-thiocyanato-imidazo2,1-b]1,3,4]thi adiazole). Materials and Methods: ROS production and expression of various apoptotic proteins were measured following 4a treatment in leukemia cell lines. Tumor animal models were used to evaluate the effect of 4a in comparison with Levamisole on progression of breast adenocarcinoma and survival. Immunohistochemistry and western blotting studies were performed to understand the mechanism of 4a action both ex vivo and in vivo. Results: We have determined the IC50 value of 4a in many leukemic and breast cancer cell lines and found CEM cells most sensitive (IC50 5 mu M). Results showed that 4a treatment leads to the accumulation of ROS. Western blot analysis showed upregulation of pro-apoptotic proteins t-BID and BAX, upon treatment with 4a. Besides, dose-dependent activation of p53 along with FAS, FAS-L, and cleavage of CASPASE-8 suggest that it induces death receptor mediated apoptotic pathway in CEM cells. More importantly, we observed a reduction in tumor growth and significant increase in survival upon oral administration of 4a (20 mg/kg, six doses) in mice. In comparison, 4a was found to be more potent than its parental analogue Levamisole based on both ex vivo and in vivo studies. Further, immunohistochemistry and western blotting studies indicate that 4a treatment led to abrogation of tumor cell proliferation and activation of apoptosis by the extrinsic pathway even in animal models. Conclusion: Thus, our results suggest that 4a could be used as a potent chemotherapeutic agent.

Optical, electrochemical and morphological investigations of poly (3,4-propylenedioxythiophene)-sultone (PProDOT-S) thin films

In this paper, we have carried out thin film characterization of poly(3,4-propylenedioxythiophene)-sultone (PProDOT-S), a derivative of electrochromic poly(3,4-propylenedioxythiophene) (PProDOT). PProDOT-S was deposited onto transparent conducting oxide coated glass substrates by solution casting method. Single wavelength spectrophotometry is used to monitor the switching speed and contrast ratio at maximum wavelength (lambda (max)). The percentage transmittance at the lambda (max) of the neutral polymer is monitored as a function of time when the polymer film is repeatedly switched. This experiment gives a quantitative measure of the speed with which a film is able to switch between the two states i.e. the coloured and the bleached states. PProDOT-S films were switched at a voltage of 1 center dot 9 V with a switching speed of 2 s at lambda (max) of 565 nm and showed a contrast of similar to 37%. Cyclic voltammetry performed at different scan rates have shown the characteristic anodic and cathodic peaks. The structural investigations of PProDOT-S films by IR spectra were in good agreement with previously reported results. Raman spectra of PProDOT-S showed a strong Raman peak at 1509 cm (-aEuro parts per thousand 1) and a weak peak at 1410 cm (-aEuro parts per thousand 1) due to the C = C asymmetric and symmetric stretching vibrations of thiophene rings. The morphological investigations carried out by using scanning electron microscope (SEM) of polymer films have shown that these polymers are found to be arranged in dense packed clusters with non-uniform distribution having an average width and length of 95 nm and 160 nm, respectively.

An approach to chiral amino acids via reductive amination of ketones: hydride reduction of 1-(S)-phenethyl amine derived Schiff bases of C-protected alpha-keto acids

Various 1-acyl-2,4,10-trioxaadamantanes were prepared from the corresponding 1-methoxycarbonyl derivatives, via conversion to the N-acylpiperidine derivatives followed by reaction with a Grignard reagent in refluxing THF. These alpha-keto orthoformates were converted to the corresponding imines with 1-(S)-phenethyl amine (TiCl4/Et3N/toluene/reflux), with the Schiff bases being reduced further with NaBH4 (MeOH/0 degrees C) into the corresponding 1-(S)-phenethyl amines (diastereomeric excess 91:9 by NMR). Hydrogenolysis of the phenethyl group (Pd-C/MeOH) finally led to the 1-(aminoalkyl)trioxaadamantanes, which are chiral C-protected alpha-amino acids, in excellent overall yields. (C) 2012 Elsevier Ltd. All rights reserved.

Random copolymers consisting of dithienylcyclopentadienone, thiophene and benzothiadiazole for bulk heterojunction solar cells

Novel random copolymers containing dithienylcyclopentadienone, thiophene and benzothiadiazole were synthesized and photovoltaic properties of these materials were evaluated. Thermal, structural, optical and electrochemical characterization of the synthesized copolymers was carried out. These thermally stable copolymers are solution processable unlike the homopolymer. The absorption spectra indicated that with the incorporation of alkyl chains in the thiophene moiety, the onset of absorption increases and hence band gap decreases (1.47 eV to 1.41 eV). Bulk heterojunction solar cells were fabricated with the blend of copolymer and phenyl-C61-butyric acid methyl ester (PCBM) as the active material and device parameters were extracted. The copolymer consists of alkyl thiophene exhibit higher open circuit voltage than the copolymer consisting of thiophene moiety. (c) 2012 Elsevier B.V. All rights reserved.

Design and Synthesis of a Functional Derivative of the Triazinium Cation and Its Rhodium Complex that Shows Photoinduced DNA Cleavage Activity and Photocytotoxicity

The design and synthesis of an intensely blue rhodium(III) complex 3]+ of a new N,N-donor ligand, 8-(quinolin-8-ylamino)pyrido2,1-c]1,2,4]benzotriazin-11-ium, 2]+, which contains a planar pendant triazinium arm, is described. Structural characterization for 3]+ was carried out by using various spectroscopic techniques and single-crystal X-ray crystallography. The organometallic rhodium(III) compound shows a ligand-based reversible reduction at 0.65 V. The electrochemically reduced compound displays a single-line EPR spectrum that signifies the formation of ligand-based free radicals. Compound 3]+ shows a binding propensity to calf thymus DNA to give a Kapp value of 6.05X105 M1. The parent triazinium salt, pyrido2,1-c]1,2,4]benzotriazin-11-ium 1]+ and the ligand salt 2]+ exhibit photoinduced cleavage of DNA in UV-A light, whereas the reference Rh complex 3]+ photocleaves DNA with red light (647.1 nm). The compounds show photonuclease activities under both aerobic and anaerobic conditions. Mechanistic investigations under aerobic conditions with several inhibitors indicate the formation of hydroxyl radicals by means of a photoredox pathway. Under anaerobic conditions, it is believed that a photoinduced oxidation of DNA mechanism is operative. Compound 3]+ exhibits photocytotoxicity in HeLa cervical cancer cells to give IC50 values of (12+/-0.9) mu M in UV-A light at 365 nm and (31.4+/-1.1) mu M in the dark.

Stabilization and Structural Alteration of the G-Quadruplex DNA Made from the Human Telomeric Repeat Mediated by Troger's Base Based Novel Benzimidazole Derivatives

Ligand-induced stabilization of the G-quadruplex DNA structure derived from the single-stranded 3'-overhang of the telomeric DNA is an attractive strategy for the inhibition of the telomerase activity. The agents that can induce/stabilize a DNA sequence into a G-quadruplex structure are therefore potential anticancer drugs. Herein we present the first report of the interactions of two novel bisbenzimidazoles (TBBz1 and TBBz2) based on Troger's base skeleton with the G-quadruplex DNA (G4DNA). These Troger's base molecules stabilize the G4DNA derived from a human telomeric sequence. Evidence of their strong interaction with the G4DNA has been obtained from CD spectroscopy, thermal denaturation, and UV-vis titration studies. These ligands also possess significantly higher affinity toward the G4DNA over the duplex DNA. The above results obtained are in excellent agreement with the biological activity, measured in vitro using a modified TRAP assay. Furthermore, the ligands are selectively more cytotoxic toward the cancerous cells than the corresponding noncancerous cells. Computational studies suggested that the adaptive scaffold might allow these ligands to occupy not only the G-quartet planes but also the grooves of the G4DNA.

Grafting of Dispersants on MoS2 Nanoparticles in Base Oil Lubrication of Steel

Solid lubricant nanoparticles in suspension in oil are good lubricating options for practical machinery. In this article, we select a range of dispersants, based on their polar moieties, to suspend 50-nm molybdenum disulfide particles in an industrial base oil. The suspension is used to lubricate a steel on steel sliding contact. A nitrogen-based polymeric dispersant (aminopropyl trimethoxy silane) with a free amine group and an oxygen-based polymeric dispersant (sorbital monooleate) when grafted on the particle charge the particle negatively and yield an agglomerate size which is almost the same as that of the original particle. Lubrication of the contact by these suspensions gives a coefficient of friction in the similar to 0.03 range. The grafting of these surfactants on the particle is shown here to be of a chemical nature and strong as the grafts survive mechanical shear stress in tribology. Such grafts are superior to those of other silane-based test surfactants which have weak functional groups. In the latter case, the particles bereft of strong grafts agglomerate easily in the lubricant and give a coefficient of friction in the 0.08-0.12 range. This article investigates the mechanism of frictional energy dissipation as influenced by the chemistry of the surfactant molecule.