Division of Medicinal Chemistry Abstracts-235th ACS National ...

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MEDI 60 Fluorescence detection of nucleic acids triggered by DNA-templated chemical reaction Kazuhiro Furukawa 1 , Hiroshi Abe 2 , Wang Jin 2 , Kazuma Oki 1 , Miwako Uda 1 , Satoshi Tsuneda 3 , and Yoshihiro Ito 2 . (1) Nano Medical Engineering Laboratory, RIKEN, Waseda University, 2-1, Hirosawa, Wako-Shi, Saitama 351-0198, Japan, k-furukawa@riken.jp, (2) RIKEN, (3) Waseda University Sequence specific detection of nucleic acids is crucial for genome study, for mRNA monitoring in living cells, and for disease diagnosis. Recently, DNA-templated chemical reactions, which produce a signal as ligation process through a quenching, FRET mechanism, catalytic hydrolysis, or catalytic transfer between two probes, are becoming general approaches for the detection of oligonucleotide sequences. However, it was difficult to eliminate the background fluorescence when the target DNA or RNA was absent. Here, we developed a new nonenzymatic phosphorothioate–iodoacetyl ligation system combined with FRET system for fluorescence detection of nucleic acids. The new chemical system discriminated a single mismatch of DNAs. In addition, a novel fluorescence activation system, which minimized the background fluorescence in the absence of target DNA, was also developed. MEDI 61 New fluorescence-based assays for identification and characterization of selective PPARα, δ(β), and γ ligands Upinder Singh, Bryan D. Marks, Hildegard C. Eliason, Deborah K. Stafslien, Jennifer M. Wilkinson, Therese De Rosier, Tina M. Hallis, Kurt W. Vogel, Guobin Miao, and William J. Frazee, Invitrogen Discovery Sciences, 501 Charmany Drive, Madison, WI 53719, Fax: 608- 204-5200, upinder.singh@invitrogen.com The peroxisome proliferator-activated receptors (PPARs), important regulators of lipid metabolism, have three sub-types with different biological functions and tissue distributions: PPARα, δ(β), and γ. Like other nuclear receptors, the activities of the PPARs are regulated both by (endogenous or exogenous) ligands and by endogenous protein coregulators (coactivators or corepressors). We have developed new competitive binding and coregulator interaction assays for each PPAR sub-type using LanthaScreen TR-FRET technology and cellular b- lactamase reporter gene assays using GeneBLAzer® technology. Ligand binding to PPARs is detected by displacement of a fluorescent PPAR ligand (tracer) from the receptor, resulting in loss of the FRET signal between the tracer and a terbium-labeled antibody to the GST tag on PPAR. Modulation of coregulator peptide binding is detected by changes in the FRET signal between a terbium-labeled antibody and a fluorescein-labeled coregulator peptide. These assays enable the discovery and evaluation of compounds that bind to and modulate PPAR activity.
MEDI 62 Caco-2 cell based assay development for tight junction modulating peptides Kelly M. Kitchens, Shobha Gopalakrishnan, John Vere, Rosa Carrasco, Min Li, Ed Oliver, Mark Ginski, Niranjan Pandey, Blake Paterson, Sefik S. Alkan, and Amir P. Tamiz, Alba Therapeutics Corporation, 800 W. Baltimore Street, Suite 400, Baltimore, MD 21201 Tight junctions maintain barrier integrity of the intestinal epithelium by regulating paracellular permeability. Epithelial barrier dysfunction is associated with a host of inflammatory and autoimmune diseases including celiac disease, irritable bowel disease, and type I diabetes. We developed in-vitro assays to study a series of paracellular permeability modulating peptides derived from zonula occludens toxin (ZOT), a protein secreted by Vibrio cholerae that transiently and reversibly opens epithelial tight junctions. The following techniques were applied using Caco-2 cells to screen various peptides for optimal compound selection: a) permeability and transepithelial electrical resistance (TEER) measurements in 24-well Transwell® format; b) cytotoxicity determination using CellTiter-Glo® cell viability assay; and c) tight junction protein reorganization using fluorescence microscopy. Our strategy has successfully identified non-toxic peptides that selectively modulate paracellular permeability for the potential treatment of autoimmune and inflammatory diseases. MEDI 63 Identification and hit to head optimization of a series of pkc theta inhibitors for t cell mediated diseases Magda Asselin, Exploratory chemistry, Wyeth Research, 401 N Middletown Rd, Pearl River, NY 10965, Fax: 845-602-5561, asselim@wyeth.com 1Chemical and Screening Sciences, Wyeth Research, 401 N. Middletown Rd. Pearl River, NY 10965. 2Inflammation and 3Chemical and Screening Sciences, Wyeth Research, 200 Cambridge Park Drive, Cambridge, MA 02140, 4Chemical and Screening Sciences, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426. Protein Kinase C theta (PKCtheta) is a critical enzyme that regulates T cell function and is required for TCR signaling leading to IL-2 production and proliferation. T cells from mice deficient in PKC theta have severely impaired T cell responses and reduced IL-2 production. The Th2 cytokines IL-4, IL-5 and IL-13 drive the pathophysiology of asthma by contributing to airway inflammation and obstruction, and IgE production. Th2 cytokine production is also significantly reduced in PKC theta deficient Th2 cell responses in vitro and in vivo. In addition, PKC theta deficient mice mount a significantly reduced lung inflammation response to antigen challenge relative to normal wild type mice, and also exhibit reduced inflammation in rodent models of arthritis and autoimmune disease. Therefore inhibitors of PKC theta may have therapeutic potential in treatment of asthma and T cell mediated immune diseases. A high-throughput screen was performed to identify PKCtheta inhibitors. The hits were characterized and prioritized based on enzyme and cell potency, evidence of binding to target, and selectivity against a panel of kinases. This poster will describe the characterization and initial hit-to-lead optimization of these novel and small molecule inhibitors of PKC theta.
Page 1 and 2: Division of Medicinal Chemistry Abs
Page 3 and 4: discovery of S/GSK364735 was a resu
Page 5 and 6: compounds was then performed target
Page 7 and 8: MEDI 13 Potent, brain-penetrant, hy
Page 9 and 10: predominately in the liver, leads t
Page 11 and 12: Candidate Optimization Department,
Page 13 and 14: acceptor atoms as the core componen
Page 15 and 16: Prostaglandin (PG) D 2 is an allerg
Page 17 and 18: polymerization, as described, by pr
Page 19 and 20: MEDI 34 Pyrogallol and its analogs
Page 21 and 22: Nicos A. Petasis 1 , Jasim Uddin 1
Page 23 and 24: Yong-Gil Kim, Joon Heo, Mi-Kyung Ji
Page 25 and 26: A new class of potent NK1 receptor
Page 27 and 28: The significant antiviral propertie
Page 29 and 30: Laboratories, West Point, PA 19486,
Page 31: MEDI 58 Preparation and antiviral a
Page 35 and 36: FMS-like tyrosine kinase 3 (FLT3) r
Page 37 and 38: MEDI 70 Synthesis of bisphosphonate
Page 39 and 40: ing. These observations suggest a p
Page 41 and 42: MEDI 77 Probing the structure-activ
Page 43 and 44: B-Raf kinase plays a critical role
Page 45 and 46: Gal-CS was used to prepare nanopart
Page 47 and 48: MEDI 88 Trifluoromethyl substituted
Page 49 and 50: MEDI 92 Discovery of novel small mo
Page 51 and 52: MEDI 96 Synthesis and antiprolifera
Page 53 and 54: MEDI 99 Development of novel antica
Page 55 and 56: MEDI 103 Discovery of N-aryl-9-oxo-
Page 57 and 58: Compounds that interfere with micro
Page 59 and 60: Carbonyl reductase (CR) has been im
Page 61 and 62: Apoptosis is a process of cell deat
Page 63 and 64: MEDI 120 Novel purine based "atypic
Page 65 and 66: MEDI 124 Efficient removal of ruthe
Page 67 and 68: library approach using technology-e
Page 69 and 70: MEDI 131 Synthesis and biological e
Page 71 and 72: MEDI 135 Identification of AT-1002
Page 73 and 74: Spectroscopic evidence was used to
Page 75 and 76: MEDI 142 Molecular basis for irreve
Page 77 and 78: MEDI 146 Effect of fluorine on subs
Page 79 and 80: MEDI 151 Overview of newer approach
Page 81 and 82: MEDI 156 Defining structure-activit
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MEDI 160 Bivalent inhibitors of P-g
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MEDI 164 Molecular basis for effica
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MEDI 167 Discovery of the highly po
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highly asymmetric, closely packed d
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4/WP14-3, Sumneytown Pike, West Poi
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MEDI 179 Design, synthesis, and eva
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MEDI 182 Substituted-pyrrole 2-amin
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MEDI 186 Discovery and optimization
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phosphatase SHIP. Bioassay guided f
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epibatidine for nicotinic channels.
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derivative with striking solubility
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MEDI 203 Core-modified mannopeptimy
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MEDI 207 Enhancing the kinetic prof
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hydroxyphenyl)piperazin-1-yl)butyl)
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migration of people from these area
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Schistosomiasis is, after malaria,
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-Ketoacyl-ACP-synthase III (FabH) h
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MEDI 225 Synthesis of the analog of
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MEDI 229 Structure-based virtual sc
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MEDI 234 TG100801: A prodrug for th
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In the past, large collections of c
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approach to the treatment of autoim
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logPe values. The residual mean squ
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Oligo-chitosan (OCS) which is a kin
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characterization of novel muscarini
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MEDI 257 Rigid analogs of 4,4-diary
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MEDI 261 Strategies toward improvin
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disease. It is generally accepted t
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(BBB). Our preliminary in vitro dat
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It is well-documented that androgen
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MEDI 276 Investigating the manipula
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were screened by FACS sarin labeled
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MEDI 285 Design, synthesis and biol
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equipment set-up and large scale ma
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Significant effort has been directe
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esearch was supported by funds from
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synthesized a series of carbamoylch
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proceeded more rapidly by switching
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genes. With the understanding of th
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MEDI 310 Optimized methods for the
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Coupled with crystallographic data,
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MEDI 317 Design and synthesis of hy
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MEDI 320 Synthesis and antibacteria
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DTPA. Incorporation of the nitro fu
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MEDI 328 The mechanism of bioreduct
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esistance, there is an urgent need
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Giving the Rule-of-5 a more accurat
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MEDI 338 Structure guided design of
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MEDI 342 Synthesis of peptide-amilo
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MEDI 346 Design, synthesis, and ant
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