Publications (33)146.77 Total impact
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Dataset: JACS - Wei04si
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Article: A One-Pot Selective Synthesis of N-Boc Protected Secondary Amines: Tandem Direct Reductive Amination/N-Boc Protection.
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ABSTRACT: A one-pot tandem direct reductive amination of aldehydes with primary amines resulting in N-Boc secondary amines using a (Boc)(2)O/sodium triacetoxyborohydride (STAB) system is reported. The tandem procedure is efficient, selective, and versatile, giving excellent yields of N-Boc protected secondary amines even in those cases where the products are prone to intramolecular lactamization.Tetrahedron 09/2012; 68(35):7056-7062. · 3.03 Impact Factor -
Article: Insights from comprehensive multiple receptor docking to HDAC8.
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ABSTRACT: A systematic investigation of the available crystal structures of HDAC8 and of the influence of different receptor structures and docking protocols is presented. The study shows that the open conformation of HDAC8 may be preferred by ligands with flexible surface binding groups, as such a conformation allows the ligands to minimize their exposure to solvent upon binding. This observation allowed us to rationalize the excellent potency of pyrazole-based inhibitors compared to that of isoxazole-based inhibitors.Journal of Molecular Modeling 03/2012; 18(8):3927-39. · 1.80 Impact Factor -
Article: Design, synthesis, docking, and biological evaluation of novel diazide-containing isoxazole- and pyrazole-based histone deacetylase probes.
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ABSTRACT: The design, synthesis, docking, and biological evaluation of novel potent HDAC3 and HDAC8 isoxazole- and pyrazole-based diazide probes suitable for binding ensemble profiling with photoaffinity labeling (BEProFL) experiments in cells is described. Both the isoxazole- and pyrazole-based probes exhibit low nanomolar inhibitory activity against HDAC3 and HDAC8, respectively. The pyrazole-based probe 3f appears to be one of the most active HDAC8 inhibitors reported in the literature with an IC(50) of 17 nM. Our docking studies suggest that unlike the isoxazole-based ligands the pyrazole-based ligands are flexible enough to occupy the second binding site of HDAC8. Probes/inhibitors 2b, 3a, 3c, and 3f exerted the antiproliferative and neuroprotective activities at micromolar concentrations through inhibition of nuclear HDACs, indicating that they are cell permeable and the presence of an azide or a diazide group does not interfere with the neuroprotection properties, or enhance cellular cytotoxicity, or affect cell permeability.Journal of Medicinal Chemistry 06/2011; 54(13):4350-64. · 4.80 Impact Factor -
Book: In Silico Modeling and its Applications on Biomolecules
04/2011; LAP LAMBERT Academic Publishing Germany., ISBN: 978- 3844328233 -
Article: An angiotensin I-converting enzyme mutation (Y465D) causes a dramatic increase in blood ACE via accelerated ACE shedding.
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ABSTRACT: Angiotensin I-converting enzyme (ACE) metabolizes a range of peptidic substrates and plays a key role in blood pressure regulation and vascular remodeling. Thus, elevated ACE levels may be associated with an increased risk for different cardiovascular or respiratory diseases. Previously, a striking familial elevation in blood ACE was explained by mutations in the ACE juxtamembrane region that enhanced the cleavage-secretion process. Recently, we found a family whose affected members had a 6-fold increase in blood ACE and a Tyr465Asp (Y465D) substitution, distal to the stalk region, in the N domain of ACE. HEK and CHO cells expressing mutant (Tyr465Asp) ACE demonstrate a 3- and 8-fold increase, respectively, in the rate of ACE shedding compared to wild-type ACE. Conformational fingerprinting of mutant ACE demonstrated dramatic changes in ACE conformation in several different epitopes of ACE. Cell ELISA carried out on CHO-ACE cells also demonstrated significant changes in local ACE conformation, particularly proximal to the stalk region. However, the cleavage site of the mutant ACE--between Arg1203 and Ser1204--was the same as that of WT ACE. The Y465D substitution is localized in the interface of the N-domain dimer (from the crystal structure) and abolishes a hydrogen bond between Tyr465 in one monomer and Asp462 in another. The Y465D substitution results in dramatic increase in the rate of ACE shedding and is associated with significant local conformational changes in ACE. These changes could result in increased ACE dimerization and accessibility of the stalk region or the entire sACE, thus increasing the rate of cleavage by the putative ACE secretase (sheddase).PLoS ONE 01/2011; 6(10):e25952. · 4.09 Impact Factor -
Article: Binding ensemble profiling with photoaffinity labeling (BEProFL) approach: mapping the binding poses of HDAC8 inhibitors.
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ABSTRACT: A binding ensemble profiling with (f)photoaffinity labeling (BEProFL) approach that utilizes photolabeling of HDAC8 with a probe containing a UV-activated aromatic azide, mapping of the covalent modifications by liquid chromatography-tandem mass spectrometry, and a computational method to characterize the multiple binding poses of the probe is described. By use of the BEProFL approach, two distinct binding poses of the HDAC8 probe were identified. The data also suggest that an "upside-down" pose with the surface binding group of the probe bound in an alternative pocket near the catalytic site may contribute to the binding.Journal of Medicinal Chemistry 11/2009; 52(22):7003-13. · 4.80 Impact Factor -
Article: Cheminformatics Approaches to Virtual Screening Cheminformatics Approaches to Virtual Screening . Edited by Alexandre Varnek (Louis Pasteur University of Strasbourg) and Alexander Tropsha (University of North Carolina at Chapel Hill). Royal Society of Chemistry: Cambridge. 2008. xvi + 338 pp. $189.00. ISBN 978-0-85404-144-2 .
Journal of the American Chemical Society 03/2009; · 9.91 Impact Factor -
Article: Molecular modeling, synthesis, and activity studies of novel biaryl and fused-ring BACE1 inhibitors.
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ABSTRACT: A series of transition state analogues of beta-secretases 1 and 2 (BACE1, 2) inhibitors containing fused-ring or biaryl moieties were designed computationally to probe the S2 pocket, synthesized, and tested for BACE1 and BACE2 inhibitory activity. It has been shown that unlike the biaryl analogs, the fused-ring moiety is successfully accommodated in the BACE1 binding site resulting in the ligands with excellent inhibitory activity. Ligand 5b reduced 65% of Abeta40 production in N2a cells stably transfected with Swedish human APP.Bioorganic & medicinal chemistry letters 11/2008; 19(1):264-74. · 2.65 Impact Factor -
Article: Receptor-based modeling and 3D-QSAR for a quantitative production of the butyrylcholinesterase inhibitors based on genetic algorithm.
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ABSTRACT: Three-dimensional quantitative structure-activity relationship (3D-QSAR) models have been constructed using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) for a series of structurally related steroidal alkaloids as butyrylcholinesterase (BuChE) inhibitors. Docking studies were employed to position the inhibitors into the BuChE active site to determine the most probable binding mode. The strategy was to explore multiple inhibitor conformations in producing a more reliable 3D-QSAR model. These multiple conformations were derived using the FlexS program. The conformation selection step for CoMFA was done by genetic algorithm. The genetic algorithm based CoMFA approach was found to be the best. Both CoMFA and CoMSIA yielded significant cross-validated q(2) values of 0.701 and 0.627 and the r(2) values of 0.979 and 0.982, respectively. These statistically significant models were validated by a test set of five compounds. Comparison of CoMFA and CoMSIA contour maps helped to identify structural requirements for the inhibitors and serves as a basis for the design of the next generation of the inhibitor analogues. The results demonstrate that the combination of ligand-based and receptor-based modeling with use of a genetic algorithm is a powerful approach to build 3D-QSAR models. These data can be used for the lead optimization process with respect to inhibition enhancement which is important for the drug discovery and development for Alzheimer's disease.Journal of Chemical Information and Modeling 06/2008; 48(5):1092-103. · 4.68 Impact Factor -
Article: 5-tert-butyl-N-pyrazol-4-yl-4,5,6,7-tetrahydrobenzo[d]isoxazole-3-carboxamide derivatives as novel potent inhibitors of Mycobacterium tuberculosis pantothenate synthetase: initiating a quest for new antitubercular drugs.
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ABSTRACT: Pantothenate synthetase (PS) is one of the potential new antimicrobial targets that may also be useful for the treatment of the nonreplicating persistent forms of Mycobacterium tuberculosis. In this Letter we present a series of 5- tert-butyl- N-pyrazol-4-yl-4,5,6,7-tetrahydrobenzo[ d]isoxazole-3-carboxamide derivatives as novel potent Mycobacterium tuberculosis PS inhibitors, their in silico molecular design, synthesis, and inhibitory activity.Journal of Medicinal Chemistry 05/2008; 51(7):1999-2002. · 5.25 Impact Factor -
Article: Phosphatidylinositol ether lipid analogues that inhibit AKT also independently activate the stress kinase, p38alpha, through MKK3/6-independent and -dependent mechanisms.
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ABSTRACT: Previously, we identified five active phosphatidylinositol ether lipid analogues (PIAs) that target the pleckstrin homology domain of Akt and selectively induce apoptosis in cancer cells with high levels of Akt activity. To examine specificity, PIAs were screened against a panel of 29 purified kinases. No kinase was inhibited, but one isoform of p38, p38alpha, was uniformly activated 2-fold. Molecular modeling of p38alpha revealed the presence of two regions that could interact with PIAs, one in the activation loop and a heretofore unappreciated region in the upper lobe that resembles a pleckstrin homology domain. In cells, two phases of activation were observed, an early phase that was independent of the upstream kinase MKK3/6 and inhibited by the p38 inhibitor SB203580 and a latter phase that was coincident with MKK3/6 activation. In short term xenograft experiments that employed immunohistochemistry and immunoblotting, PIA administration increased phosphorylation of p38 but not MKK3/6 in tumors in a statistically significant manner. Although PIAs rapidly activated p38 with similar time and dose dependence as Akt inhibition, p38 activation and Akt inhibition were independent events induced by PIAs. Using SB203580 or p38alpha(-/-) cells, we showed that p38alpha is not required for PIA-induced apoptosis but is required for H(2)O(2)- and anisomycin-induced apoptosis. Nonetheless, activation of p38a contributes to PIA-induced apoptosis, because reconstitution of p38a into p38alpha(-/-) cells increased apoptosis. These studies indicate that p38alpha is activated by PIAs through a novel mechanism and show that p38alpha activation contributes to PIA-induced cell death. Independent modulation of Akt and p38alpha could account for the profound cytotoxicity of PIAs.Journal of Biological Chemistry 10/2007; 282(37):27020-9. · 4.77 Impact Factor -
Article: Phosphatidylinositol Ether Lipid Analogues That Inhibit AKT Also Independently Activate the Stress Kinase, p38α, through MKK3/6-independent and -dependent Mechanisms
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ABSTRACT: Previously, we identified five active phosphatidylinositol ether lipid analogues (PIAs) that target the pleckstrin homology domain of Akt and selectively induce apoptosis in cancer cells with high levels of Akt activity. To examine specificity, PIAs were screened against a panel of 29 purified kinases. No kinase was inhibited, but one isoform of p38, p38α, was uniformly activated 2-fold. Molecular modeling of p38α revealed the presence of two regions that could interact with PIAs, one in the activation loop and a heretofore unappreciated region in the upper lobe that resembles a pleckstrin homology domain. In cells, two phases of activation were observed, an early phase that was independent of the upstream kinase MKK3/6 and inhibited by the p38 inhibitor SB203580 and a latter phase that was coincident with MKK3/6 activation. In short term xenograft experiments that employed immunohistochemistry and immunoblotting, PIA administration increased phosphorylation of p38 but not MKK3/6 in tumors in a statistically significant manner. Although PIAs rapidly activated p38 with similar time and dose dependence as Akt inhibition, p38 activation and Akt inhibition were independent events induced by PIAs. Using SB203580 or p38α-/- cells, we showed that p38α is not required for PIA-induced apoptosis but is required for H2O2- and anisomycin-induced apoptosis. Nonetheless, activation of p38a contributes to PIA-induced apoptosis, because reconstitution of p38a into p38α-/- cells increased apoptosis. These studies indicate that p38α is activated by PIAs through a novel mechanism and show that p38α activation contributes to PIA-induced cell death. Independent modulation of Akt and p38α could account for the profound cytotoxicity of PIAs.Journal of Biological Chemistry 09/2007; 282(37):27020-27029. · 4.77 Impact Factor -
Article: Chemical medicine: novel 10-substituted cytisine derivatives with increased selectivity for alpha4beta2 nicotinic acetylcholine receptors.
ChemMedChem 09/2007; 2(8):1157-61. · 3.15 Impact Factor -
Article: Structure-based design leads to the identification of lithium mimetics that block mania-like effects in rodents. possible new GSK-3beta therapies for bipolar disorders.
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ABSTRACT: More than two million American adults, or approximately one percent of the population 18 years or older, suffer from bipolar disorder. Current treatments include the so-called "mood stabilizers," lithium and valproic acid. Both are relatively dated drugs that are only partially effective and produce various undesirable side effects including weight gain. Based upon continued efforts to understand the molecular target for lithium, it now appears that specific inhibitors of the enzyme glycogen synthase kinase-3beta (GSK-3beta) may mimic the therapeutic action of mood stabilizers and might therefore allow for the design of improved drugs for treating patients with bipolar disorder as well as certain neurodegenerative disorders. Furthermore, the pro-apoptotic properties of the GSK-3 enzyme suggest the possible use of such inhibitors as neuroprotective agents. In fact, neuroprotection may contribute to the treatment of mood disorders. The present chemistry, modeling, and biology efforts have identified 3-benzofuranyl-4-indolylmaleimides as potent and relatively selective GSK-3beta inhibitors. The best ligand in this series (having a Ki value of 4.6 nM against GSK-3beta) was studied in a novel mouse model of mania that has recently been validated with several clinically effective mood stabilizers. This study presents the first demonstration of the efficacy of a GSK-3beta inhibitor in this mouse model of mania. Selective brain penetrable GSK-3 ligands like those described herein become valuable research tools in better defining the role of this multifaceted kinase in both physiological and pathophysiological events.Journal of the American Chemical Society 08/2007; 129(26):8328-32. · 9.91 Impact Factor -
Article: Benzothiophene selective estrogen receptor modulators with modulated oxidative activity and receptor affinity.
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ABSTRACT: The regulation of estrogenic and antiestrogenic effects of selective estrogen receptor modulators (SERMs) is thought to underlie their clinical use. Most SERMs are polyaromatic phenols susceptible to oxidative metabolism to quinoids, which are proposed to be genotoxic. Conversely, the redox reactivity of SERMs may contribute to antioxidant and chemopreventive mechanisms, providing a new approach to improve the therapeutic properties of SERMs. An improved synthetic strategy was developed to generate a family of benzothiophene SERMs. Using computational modeling methods and measurements of antioxidant activity and estrogen receptor (ER) ligand binding, this SERM family was shown to provide both a range of ERalpha/ERbeta selectivity from 1.2- to 67-fold and a range of redox activity. Antioxidant activity was successfully modulated by varying a substituent remote from the OH group; the source of the antioxidant capacity. An efficient synthetic procedure is reported yielding benzothiophene SERMs wherein redox activity and ER affinity are modulated.Journal of Medicinal Chemistry 06/2007; 50(11):2682-92. · 5.25 Impact Factor -
Article: Computational evidence for the ligand selectivity to the alpha4beta2 and alpha3beta4 nicotinic acetylcholine receptors.
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ABSTRACT: The homology models of the alpha4beta2 and alpha3beta4 nicotinic acetylcholine receptors (nAChRs) suggest that the two nAChR subtypes are different in their ligand-binding pockets due to the non-conserved residues in the beta-subunits. The docking of nicotine, epibatidine, A-84543, and the two analogs of A-84543 ligands 1 and 2 to the homology models of alpha4beta2 and alpha3beta4 is presented. It is found that the protonated amino groups of these ligands bind to the alpha-subunits, whereas the remaining parts of the ligands bind to the beta-subunits. The two non-conserved amino acids Lys77 and Phe117 in the beta2-subunit corresponding to Ile77 and Gln117 in the beta4-subunit are identified to be the key players determining the binding modes of the ligands. We demonstrate how the increase in the number of the atoms connecting the pyrrolidine and pyridine rings in A-84543, 1, and 2, and an introduction of the alkynyl substituent in the pyridine ring affect the binding and shift the selectivity of these ligands toward the beta2-containing receptors. Further improvement in affinity and selectivity in this and other series of the ligands may be achieved by designing molecules that would specifically target the non-conserved regions in nAChRs.Bioorganic & Medicinal Chemistry 01/2007; 14(23):7936-42. · 2.92 Impact Factor -
Article: Improved 3D-QSAR CoMFA of the dopamine transporter blockers with multiple conformations using the genetic algorithm.
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ABSTRACT: A 3D-QSAR/CoMFA was performed for a series of 42 piperidine-based dopamine transporter (DAT) blockers. The overall process consisted of three major steps: (1) a pharmacophore model was built using the Genetic Algorithm Similarity Program (GASP); (2) the Flexible Superposition (FlexS) technique was applied to generate multiple conformations for each of the ligands based on the pharmacophore; (3) the Genetic Algorithm was employed to optimize the selection of the ligand conformations for the CoMFA modeling. The CoMFA models were found to be more detailed in the putative binding site by exploring multiple conformations of each ligand. The comparison of the contour maps shows that, in general, these models are comparable and the differences between them result from the ability of the flexible 3alpha-substituents of the ligands to adopt multiple conformations satisfying the same pharmacophore model. These findings provide guidance for the design and improvement of compounds with DAT activity, which is important for the development of a treatment of cocaine addiction and certain neurological disorders.Bioorganic & Medicinal Chemistry Letters 01/2007; 16(24):6267-72. · 2.55 Impact Factor -
Article: Highly potent and specific GSK-3beta inhibitors that block tau phosphorylation and decrease alpha-synuclein protein expression in a cellular model of Parkinson's disease.
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ABSTRACT: Research by Klein and co-workers suggests that the inhibition of GSK-3beta by small molecules may offer an important strategy in the treatment of a number of central nervous system (CNS) disorders including Alzheimer's disease, Parkinson's disease, and bipolar disorders. Based on results from kinase-screening assays that identified a staurosporine analogue as a modest inhibitor of GSK-3beta, a series of 3-indolyl-4-indazolylmaleimides was prepared for study in both enzymatic and cell-based assays. Most strikingly, whereas we identified ligands having poor to high potency for GSK-3beta inhibition, only ligands with a Ki value of less than 8 nM, namely maleimides 18 and 22, were found to inhibit Tau phosphorylation at a GSK-3beta-specific site (Ser 396/404). Accordingly, maleimides 18 and 22 may protect neuronal cells against cell death by decreasing the level of alpha-Syn protein expression. We conclude that the GSK-3beta inhibitors described herein offer promise in defending cells against MPP+-induced neurotoxicity and that such compounds will be valuable to explore in animal models of Parkinson's disease as well as in other Tau-related neurodegenerative disease states.ChemMedChem 03/2006; 1(2):256-66. · 3.15 Impact Factor -
Article: Novel HDAC inhibitors with radiosensitizing properties.
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ABSTRACT: The members of the histone deacetylase (HDAC) family play important roles in various cellular processes, including transcriptional regulation, cell proliferation, differentiation and apoptosis. Inhibitors of histone deacetylases are emerging as an important new class of chemotherapeutic agents. As such, identifying stable and potent chemical HDAC inhibitory compounds is an important focus for translational research. Here we report the results of a rational drug design of novel HDAC inhibitors with potential for sensitizing cancer cells to radiation therapy. Over 60 HDAC inhibitor analogues incorporating a urea backbone and the hydroxamic acid end moiety were designed and screened. Six were found to confer 50% inhibition of HDAC enzyme activity at nanomolar concentrations. These candidate HDAC inhibitors inhibited cell proliferation at the ranges of IC50 10-50 microM in various cancer cells, including prostate (PC-3), breast (MCF-7) and head and neck squamous carcinoma (SQ-20B). Furthermore, radiation clonogenic survival assays revealed that these compounds possess radiosensitizing properties that are cell type-specific. The data support the further investigation of these HDAC inhibitors for use as sensitizing agents with potential for clinical application.Radiation Research 06/2005; 163(5):488-93. · 2.68 Impact Factor
Top co-authors
Top Journals
Institutions
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2005–2012
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University of Illinois at Chicago
- • Department of Medicinal Chemistry and Pharmacognosy
- • College of Pharmacy
Chicago, IL, USA -
Sanford-Burnham Medical Research Institute
La Jolla, CA, USA
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2007
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National Institutes of Health
- Center for Cancer Research
Bethesda, MD, USA
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2002
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Georgetown University
- Department of Neurology
Washington, D. C., DC, USA
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