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151.
Annedi SC Ramnauth J Cossette M Maddaford SP Dove P Rakhit S Andrews JS Porreca F 《Bioorganic & medicinal chemistry letters》2012,22(7):2510-2513
A novel class of 1,7-disubstituted 2,3,4,5-tetrahydro-1H-benzo[b]azepine derivatives was designed, synthesized and evaluated as human nitric oxide synthase (NOS) inhibitors. Structure-activity relationship studies based on various basic amine side chains attached at the 1-position of the 2,3,4,5-tetrahydro-1H-benzo[b]azepine ring led to the identification of several potent and highly selective inhibitors (17, 18, 25, (±)-39, and (±)-40) of human neuronal NOS. The potential therapeutic application of one of these new selective nNOS inhibitors (17) was demonstrated in an in vivo spinal nerve ligation model of neuropathic pain, and various in vitro safety pharmacology studies such as the hERG K(+) channel inhibition assay and high throughput broad screen (minimal activity at 79 receptors/transporters/ion channels). 相似文献
152.
Verbanac D Jain SC Jain N Chand M Cipčić Paljetak H Matijašić M Perić M Stepanić V Saso L 《Bioorganic & medicinal chemistry》2012,20(10):3180-3185
Xanthones and their thio-derivatives are a class of pleiotropic compounds with various reported pharmacological and biological activities. Although these activities are mainly determined in laboratory conditions, the class itself has a great potential to be utilized as promising chemical scaffold for the synthesis of new drug candidates. One of the main obstacles in utilization of these compounds was related to the difficulties in their chemical synthesis. Most of the known methods require two steps, and are limited to specific reagents not applicable to a large number of starting materials. In this paper a new and improved method for chemical synthesis of xanthones is presented. By applying a new procedure, we have successfully obtained these compounds with the desired regioselectivity in a shorter reaction time (50s) and with better yield (>80%). Finally, the preliminary in vitro screenings on different bacterial species and cytotoxicity assessment, as well as in silico activity evaluation were performed. The obtained results confirm potential pharmacological use of this class of molecules. 相似文献
153.
Kuldeep K. Roy Santoshkumar Tota Tusha Tripathi Subhash Chander Chandishwar Nath Anil K. Saxena 《Bioorganic & medicinal chemistry》2012,20(21):6313-6320
The optimization of our previous lead compound 1 (AChE IC50 = 3.31 μM) through synthesis and pharmacology of a series of novel carbamates is reported. The synthesized compounds were evaluated against mouse brain AChE enzyme using the colorimetric method described by Ellman et al. The three compounds 6a (IC50 = 2.57 μM), 6b (IC50 = 0.70 μM) and 6i (IC50 = 2.56 μM) exhibited potent in vitro AChE inhibitory activities comparable to the drug rivastigmine (IC50 = 1.11 μM). Among them, the compound 6b has been selected as possible optimized lead for further neuropharmacological studies. In addition, the AChE–carbamate Michaelis complexes of these potent compounds including rivastigmine and ganstigmine have been modeled using covalent docking protocol of GOLD and important direct/indirect interactions contributing to stabilization of the AChE–carbamate Michaelis complexes have been investigated. 相似文献
154.
Chandra S Kaur M Midha S Bhatnagar R Banerjee-Bhatnagar N 《Biochemical and biophysical research communications》2006,351(3):702-707
We report the ability of N-terminal fragment of lethal factor of Bacillus anthracis to deliver genetically fused ESAT-6 (early secretory antigen target), a potent T cell antigen of Mycobacterium tuberculosis, into cytosol to elicit Cytotoxic T lymphocyte (CTL) response. In vitro Th1 cytokines data and CTL assay proved that efficient delivery of LFn.ESAT-6 occurs in cytosol, in the presence of protective antigen (PA), and leads to generation of effective CTL response. Since CTL response is essential for protection against intracellular pathogens and, it is well known that only single T cell epitope or single antigenic protein is not sufficient to elicit protective CTL response due to variation or polymorphism in MHC-I alleles among the individuals, we suggest that as a fusion protein LFn can be used to deliver multiepitopes of T cells or multiproteins which can generate effective CTLs against intracellular pathogens like M. tuberculosis. It can be used to enhance the protective efficacy of BCG vaccine. 相似文献
155.
Patole J Shingnapurkar D Padhye S Ratledge C 《Bioorganic & medicinal chemistry letters》2006,16(6):1514-1517
Schiff base conjugates of p-aminosalicylic acid have been synthesized and characterized by elemental analysis, IR and (1)H NMR spectroscopy and cyclic voltammetry. Compounds containing hydroxyl-rich side chains show enhanced antimycobacterial activity against Mycobacterium smegmatis and Mycobacterium bovis BCG. Higher ClogP values and superior radical scavenging activities are thought to be the contributing factors for their enhanced antimycobacterial activities. 相似文献
156.
Latency-Associated Nuclear Antigen of Kaposi's Sarcoma-Associated Herpesvirus (KSHV) Upregulates Survivin Expression in KSHV-Associated B-Lymphoma Cells and Contributes to Their Proliferation
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Jie Lu Subhash C. Verma Masanao Murakami Qiliang Cai Pankaj Kumar Bingyi Xiao Erle S. Robertson 《Journal of virology》2009,83(14):7129-7141
157.
Bhahwal Ali Shah Rajbir Kaur Pankaj Gupta Ajay Kumar Vijay Kumar Sethi Samar Singh Andotra Jaswant Singh Ajit Kumar Saxena Subhash Chandra Taneja 《Bioorganic & medicinal chemistry letters》2009,19(15):4394-4398
Analogues of parthenin were synthesized by substitutions at different reaction centres to establish a structure–activity relationship (SAR). Some of the molecules have displayed significant cytotoxicity in human cervical carcinoma (HeLa) and human myeloid leukemia (HL-60) cells. A few of the compounds also induced apoptosis in HL-60 cells measured in terms of sub-Go/G1 DNA fraction. Also one of the lead molecules has been shown to be the inhibitor of both telomerase and topoisomerase-II. 相似文献
158.
HIV-1 protease is an effective target for design of different types of drugs against AIDS. HIV-1 protease is also one of the few enzymes that can cleave substrates containing both proline and nonproline residues at the cleavage site. We report here the first structure of HIV-1 protease complexed with the product peptides SQNY and PIV derived by in situ cleavage of the oligopeptide substrate SQNYPIV, within the crystals. In the structure, refined against 2.0-A resolution synchrotron data, a carboxyl oxygen of SQNY is hydrogen-bonded with the N-terminal nitrogen atom of PIV. At the same time, this proline nitrogen atom does not form any hydrogen bond with catalytic aspartates. These two observations suggest that the protonation of scissile nitrogen, during peptide bond cleavage, is by a gem-hydroxyl of the tetrahedral intermediate rather than by a catalytic aspartic acid. 相似文献
159.
Christophe Bodenreider David Beer Thomas H. Keller Sebastian Sonntag Daying Wen LiJian Yap Yin Hoe Yau Susana Geifman Shochat Danzhi Huang Ting Zhou Amedeo Caflisch Xun-Cheng Su Kiyoshi Ozawa Gottfried Otting Subhash G. Vasudevan Julien Lescar Siew Pheng Lim 《Analytical biochemistry》2009,395(2):195-204
In drug discovery, the occurrence of false positives is a major hurdle in the search for lead compounds that can be developed into drugs. A small-molecular-weight compound that inhibits dengue virus protease at low micromolar levels was identified in a screening campaign. Binding to the enzyme was confirmed by isothermal titration calorimetry (ITC) and nuclear magnetic resonance (NMR). However, a structure–activity relationship study that ensued did not yield more potent leads. To further characterize the parental compound and its analogues, we developed a high-speed, low-cost, quantitative fluorescence quenching assay. We observed that specific analogues quenched dengue protease fluorescence and showed variation in IC50 values. In contrast, nonspecifically binding compounds did not quench its fluorescence and showed similar IC50 values with steep dose–response curves. We validated the assay using single Trp-to-Ala protease mutants and the competitive protease inhibitor aprotinin. Specific compounds detected in the binding assay were further analyzed by competitive ITC, NMR, and surface plasmon resonance, and the assay’s utility in comparison with these biophysical methods is discussed. The sensitivity of this assay makes it highly useful for hit finding and validation in drug discovery. Furthermore, the technique can be readily adapted for studying other protein–ligand interactions. 相似文献
160.
Sabyasachi Halder Masanao Murakami Subhash C. Verma Pankaj Kumar Fuming Yi Erle S. Robertson 《PloS one》2009,4(9)
Epstein Barr virus (EBV) is closely associated with the development of a vast number of human cancers. To develop a system for monitoring early cellular and viral events associated with EBV infection a self-recombining BAC containing 172-kb of the Epstein Barr virus genome BAC-EBV designated as MD1 BAC (Chen et al., 2005, J.Virology) was used to introduce an expression cassette of green fluorescent protein (GFP) by homologous recombination, and the resultant BAC clone, BAC-GFP-EBV was transfected into the HEK 293T epithelial cell line. The resulting recombinant GFP EBV was induced to produce progeny virus by chemical inducer from the stable HEK 293T BAC GFP EBV cell line and the virus was used to immortalize human primary B-cell as monitored by green fluorescence and outgrowth of the primary B cells. The infection, B-cell activation and cell proliferation due to GFP EBV was monitored by the expression of the B-cell surface antigens CD5, CD10, CD19, CD23, CD39, CD40 , CD44 and the intercellular proliferation marker Ki-67 using Flow cytometry. The results show a dramatic increase in Ki-67 which continues to increase by 6–7 days post-infection. Likewise, CD40 signals showed a gradual increase, whereas CD23 signals were increased by 6–12 hours, maximally by 3 days and then decreased. Monitoring the viral gene expression pattern showed an early burst of lytic gene expression. This up-regulation of lytic gene expression prior to latent genes during early infection strongly suggests that EBV infects primary B-cell with an initial burst of lytic gene expression and the resulting progeny virus is competent for infecting new primary B-cells. This process may be critical for establishment of latency prior to cellular transformation. The newly infected primary B-cells can be further analyzed for investigating B cell activation due to EBV infection. 相似文献