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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
22
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pubmed:dateCreated |
2004-10-14
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pubmed:abstractText |
The design, synthesis, and biological evaluation of potent inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1) are reported. A novel series of 3,4-dihydro-2H-[1,4]diazepino[6,7,1-hi]indol-1-ones were designed using a combination of protein structure-based drug design, molecular modeling, and structure-activity relationships (SAR). These novel submicromolar inhibitors possess a tricyclic ring system conformationally restricting the benzamide in the preferred cis orientation. The compounds were designed to optimize space-filling and atomic interactions within the NAD+ binding site of PARP-1. Previously described and newly adapted methods were applied to syntheses of these tricyclic inhibitors. Various modifications were made to the diazepinoindolones at the 6- and 7-positions in order to study this region of the active site and optimize noncovalent interactions. The electron density of derivative 28 bound to chicken PARP-1 revealed that the oxime makes a tight hydrogen bond with the catalytic gamma-carboxylate of glutamic acid (Glu) 988 in accordance with our original designs and models. Most of the compounds have been evaluated for inhibition of human PARP-1. Selected inhibitors were also tested for the ability to potentiate the cytotoxic effect of the DNA-damaging agent Topotecan.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Oct
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pubmed:issn |
0022-2623
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pubmed:author |
pubmed-author:AlmassyRobert JRJ,
pubmed-author:BoritzkiTheodore JTJ,
pubmed-author:CalabreseChris RCR,
pubmed-author:CalvertA HilaryAH,
pubmed-author:CurtinNicola JNJ,
pubmed-author:EkkersAnneA,
pubmed-author:GoldingBernard TBT,
pubmed-author:GriffinRoger JRJ,
pubmed-author:HostomskyZdenekZ,
pubmed-author:KumpfRobert ARA,
pubmed-author:KyleSuzanneS,
pubmed-author:LiJiankeJ,
pubmed-author:MaegleyKaren AKA,
pubmed-author:NewellDavid RDR,
pubmed-author:ThomasHuw DHD,
pubmed-author:TikheJayashree GJG,
pubmed-author:WangLan-ZhenLZ,
pubmed-author:WebberStephen ESE,
pubmed-author:YuXiao-HongXH,
pubmed-author:ZhangCathyC
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pubmed:issnType |
Print
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pubmed:day |
21
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pubmed:volume |
47
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
5467-81
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pubmed:dateRevised |
2010-11-18
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pubmed:meshHeading |
pubmed-meshheading:15481984-Antineoplastic Agents,
pubmed-meshheading:15481984-Azepines,
pubmed-meshheading:15481984-Cell Line, Tumor,
pubmed-meshheading:15481984-Cell Proliferation,
pubmed-meshheading:15481984-Crystallography, X-Ray,
pubmed-meshheading:15481984-Drug Design,
pubmed-meshheading:15481984-Drug Resistance, Neoplasm,
pubmed-meshheading:15481984-Drug Synergism,
pubmed-meshheading:15481984-Humans,
pubmed-meshheading:15481984-Indoles,
pubmed-meshheading:15481984-Models, Molecular,
pubmed-meshheading:15481984-Poly(ADP-ribose) Polymerases,
pubmed-meshheading:15481984-Structure-Activity Relationship,
pubmed-meshheading:15481984-Topoisomerase I Inhibitors
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pubmed:year |
2004
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pubmed:articleTitle |
Design, synthesis, and evaluation of 3,4-dihydro-2H-[1,4]diazepino[6,7,1-hi]indol-1-ones as inhibitors of poly(ADP-ribose) polymerase.
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pubmed:affiliation |
Pfizer Global R&D--La Jolla Laboratories, 10770 Science Center Drive, San Diego, California 92121, USA. jayashree.tikhe@pfizer.com
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pubmed:publicationType |
Journal Article
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