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

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MEDI 72 Synthesis and SAR studies of a novel series of T-type calcium channel blockers Yun Jeong Choe 1 , Han Na Seo 1 , Ja Youn Choi 1 , Jungahn Kim 2 , Dong Joon Choo 2 , and Jae Yeol Lee 2 . (1) Department of Chemistry, Kyung Hee University, 1 Hoegi-dong, Dongdaemoongu, Seoul 130-701, South Korea, Fax: 82-2-966-3701, whitebear48@naver.com, (2) Department of Chemistry, Kyunghee University, Seoul 130-701, South Korea For the novel, potent, and selective T-type Ca 2+ channel blockers, a series of 3, 4- dihydroquinazoline derivatives containing 1, 5-diaminopentane were prepared and evaluated for their blocking actions on T- and N-type Ca 2+ channels. As a result of the structure-activity relationship study, KYS05090 (IC 50 = 41 ± 1 nM) was found to be as potent as Kurtoxin. Herein, we will discuss the detailed SAR result of this series of compounds. MEDI 73 Thiols oxidation and covalent binding of BSA by cyclolignanic quinones are enhanced by the magnesium cation Ajay Kumar 1 , Antonio E. Alegria 1 , Pedro Sanchez-Cruz 1 , Carmelo García 1 , Fernando A. Gonzalez 2 , Aimee Orellano 2 , Beatriz Zayas 3 , and Marina Gordaliza 4 . (1) Department of Chemistry, University of Puerto Rico at Humacao, Humacao, PR 00791, Fax: 787-850-9422, a_kumar@uprh.edu, (2) Department of Chemistry, University of Puerto Rico - Rio Piedras, San Juan, PR 00931, (3) Department of Environmental Affairs, Universidad Metropolitana (UMET), San Juan, PR 00928-1150, (4) Departamento de Química Farmacéutica, Campus Miguel de Unamuno, Facultad de Farmacia, Salamanca 37007, Spain A novel cyclolignanic quinone, 7-acetyl-3,4-didemethoxy-3,4-dioxopodophyllotoxin (CLQ) inhibits topoisomerase II (TOPO II) activity. The extent of this inhibition was greater than that produced by the etoposide quinone (EQ) or etoposide. Glutathione (GSH) reduces EQ and CLQ to their corresponding semiquinones under anaerobic conditions. The later were detected by EPR spectroscopy in the presence of MgCl2 but not in its absence. Semiquinone EPR spectra change with quinone/GSH mol ratio suggesting covalent binding of GSH to the quinones. These orthoquinones react with nucleophilic groups from BSA to bind covalently BSA under anaerobic conditions. Thiol consumption and BSA binding are enhanced by MgCl2. Complex formation between the parent quinones and Mg+2 were also observed. Theoretical calculations predict the observed blue-shifts in the absorption spectra peaks when the quinones are complexed to Mg+2 and large increases in the partial positive charge of electrophilic carbons at the quinone
ing. These observations suggest a possible role of Mg+2 chelation by these quinones in increasing TOPO II thiol and/or amino/imino reactivity with these orthoquinones. MEDI 74 Synthesis of 7-substituted benzyl-5-[(3,4,5-trimethoxyphenyl)ethyl]-4-methyl- 7Hpyrrolo[2, 3-d]pyrimidin-2-amines as microtubule inhibitors Aleem Gangjee 1 , Sonali Kurup 1 , and Charles D. Smith 2 . (1) Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Ave., Pittsburgh, PA 15282, Fax: 412-396-5593, gangjee@duq.edu, (2) Department of Pharmaceutical Sciences, Medical University of South Carolina, Charleston, SC 29425 Microtubules are long protein polymers composed of α- and β-tubulin heterodimers. The crucial involvement of microtubules makes them a target for cancer chemotherapy. Antitumor agents that target microtubules are called antimitotic agents. However, several antimitotic agents have problems such as toxicity and drug resistance, hence there is a continuing effort to find novel, more effective microtubule inhibitors. Gangjee et al. previously reported 7-benzyl-5-substituted phenylethyl-4-methyl-7H- pyrrolo[2,3- d]pyrimidin-2-amines as antimitotic agents. The compounds target tubulin and have a different binding site on tubulin from that of known inhibitors. In addition to their antitumor activity, some of the compounds also reversed tumor resistance to antimitotic agents via the PgP efflux pump. The 7-benzyl substitution in these compounds was suggested to be important for activity. Using the 7-benzyl-5-(3,4,5-trimethoxyphenyl)ethyl-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-amine as the lead analog, we have explored varied substitutions on the 7-benzyl ring in order to optimize the inhibitory activity against tubulin. The design, synthesis and antimitotic activities of these compounds will be presented and discussed. MEDI 75 Synthesis of analogs of trienomycin A, a potential inhibitor of Hsp90 Geraldine Calvet, Department of Medicinal Chemistry, University of Kansas, 1251 Wescoe Hall Drive, 4070 Malott Hall, Lawrence, KS 66045, gfcalvet@yahoo.fr, and Brian Blagg, Department of Medicinal Chemistry, University of Kansas, Lawrence, KS 66045-7583 Trienomycin A is a member of the ansamycin family of antibiotics. Like geldanamycin, this molecule is a macrolactam containing an oxygenated aromatic ring. Both trienomycin A and geldanamycin have exceptional activity against several cancer cell lines. Considering the similarities between these two macrocycles, trienomycin A could be, like geldanamycin, an inhibitor of Hsp90 which is an emerging target in the treatment of cancers. The synthesis of analogs of trienomycin A will be described and the initial biological results presented.
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 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: MEDI 70 Synthesis of bisphosphonate
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
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
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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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