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

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MEDI 86 Targeting RING finger domain of HDM2 for cancer therapy Zengjian Hu and Lei Liu, Department of Computer-Aided Drug Discovery, Biogenova, Corp, 401 Rosemont Ave, 3rd Floor, Rosenstock Hall, Frederick, MD 21701 Human double minute 2 (HDM2) is by far the most studied and best understood p53-specific ubiquitin protein ligase. The C-terminal domain of HDM2, critical for its E3 ubiquitin ligase activity, was identified as the RING finger domain. Recently, a family of small molecules has been identified to inhibit HDM2's E3 activity which does not involve inhibition of the p53-HDM2 interaction. Therefore, HDM2 RING finger domain represents a new promising target for developing anticancer agents. In this study, we use structure-based virtual screening to identify novel small molecule inhibitors of HDM2 by using experimental structure of the HDM2 RING finger domain and our natural products library. The lead compounds from our studies are nonpeptide, cell permeable small molecules that specifically bind to the RING finger domain of HDM2 and will inhibit HDM2's E3 activity. And this inhibition in turn will promote and/or induce apoptosis in human cancer cells. MEDI 87 Total synthesis of new cytotoxic diterpenes Daniel Rabouin, Lionel Dumas, Eric Beaulieu, Kenza Daïri, Samuel Fortin, Eric Fournier, Gerson G. Gonzalez, Sasmita Tripathy, Sylvie Bailly, Gaetan Gagnon, Sandra Naranjo, Brigitte St-Denis, Nancy Steenaart, Jean-François Lavallee, Giorgio Attardo, Pierre Beauparlant, Xavier Billot, and Laurent Bélec, Gemin X Biotechnologies Inc, 3576 Avenue du Parc, suite 4310, Montréal, QC H2X 2H7, Canada, drabouin@geminx.com, ldumas@geminx.com We identified a diterpene of natural origin; (R)-10-hydroxy-6-methoxy-1,1,4a,7- tetramethylphenanthrene-2,9(1H,4aH)-dione , during a high throughput screening campaign. This compound induces the activation of caspase-3, an apoptotic effector. In an effort to generate derivatives of this compound we devised a synthetic methodology which allowed us to obtain a first series of analogs. In order to target some specifics analogues of general structure 1, a modified synthetic route was devised. A series of modifications on ring C was achieved by using a Wittig-Heck approach. We will describe the synthetic approaches used in this project along with examples of biologically active compounds.
MEDI 88 Trifluoromethyl substituted pyrrole 2-indolinone derivatives as tyrosine kinase inhibitors TANG Peng Cho, BIE Ping Yan, LIU Wei Li, YANG Shi Bo, ZHANG Lei, and FENG Jun, Shanghai Hengrui Pharmaceuticals Co. Ltd, 279 Wenjing Road, Shanghai 200245, China, tangpc@shhrp.com, biepy@shhrp.com Receptor tyrosine kinases (RTKs) have been implicated as therapeutic targets for the treatment of human diseases including cancers, inflammatory diseases. A series of trifluoromethyl pyrrole substituted 2-indolinone derivatives of general formula (I) as tyrosine kinase inhibitors were designed and synthesized. They were found to inhibit the tyrosine kinase activity associated with vascular endothelial growth factor receptor 2(VEGF-R2). Their biological evaluation results and structure-activity relationship will be discussed. MEDI 89 Using novobiocin analogs to probe the C-terminus of Hsp90 Alison C. Donnelly and Brian S. J. Blagg, Department of Medicinal Chemistry, The University of Kansas, 1251 Wescoe Hall Drive, Lawrence, KS 66045-7583, adonnelly@ku.edu Hsp90 is a 90 kDa member of the heat shock family of proteins that act as molecular chaperones. These proteins are essential for folding nascent polypeptides and refolding denatured or misfolded proteins. Novobiocin, an antibiotic that inhibits DNA gyrase, is known to bind the C-terminus of Hsp90 with relatively poor affinity and induce degradation of Hsp90- dependent client proteins at ~700 µM in SKBr3 cells. Studies have been performed to improve the inhibitory activity of novobiocin analogues and convert a well-known DNA gyrase inhibitor into a selective inhibitor of Hsp90. Several analogues have been synthesized that probe the contribution of the benzamide, coumarin, and sugar moieties toward Hsp90 inhibitory activity. These compounds have been evaluated in vitro and structure-activity relationships for the C- terminus of Hsp90 have been revealed
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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 and 32: MEDI 58 Preparation and antiviral a
Page 33 and 34: MEDI 62 Caco-2 cell based assay dev
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: Gal-CS was used to prepare nanopart
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
Page 83 and 84: MEDI 160 Bivalent inhibitors of P-g
Page 85 and 86: MEDI 164 Molecular basis for effica
Page 87 and 88: MEDI 167 Discovery of the highly po
Page 89 and 90: highly asymmetric, closely packed d
Page 91 and 92: 4/WP14-3, Sumneytown Pike, West Poi
Page 93 and 94: MEDI 179 Design, synthesis, and eva
Page 95 and 96: 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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