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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
15
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pubmed:dateCreated |
2008-8-8
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pubmed:abstractText |
The aromathecin or "rosettacin" class of topoisomerase I (top1) inhibitors is effectively a "composite" of the natural products camptothecin and luotonin A and the synthetic indenoisoquinolines. The aromathecins have aroused considerable interest following the isolation and total synthesis of 22-hydroxyacuminatine, a rare cytotoxic natural product containing the 12 H-5,11a-diazadibenzo[ b, h]fluoren-11-one system. We have developed two novel syntheses of this system and prepared a series of 14-substituted aromathecins as novel antiproliferative topoisomerase I poisons. These inhibitors are proposed to act via an intercalation and "poisoning" mechanism identical to camptothecin and the indenoisoquinolines. Many of these compounds possess greater antiproliferative activity and anti-top1 activity than the parent unsubstituted compound (rosettacin) and previously synthesized aromathecins, as well as greater top1 inhibitory activity than 22-hydroxyacuminatine. In addition to potentially aiding solubility and localization to the DNA-enzyme complex, nitrogenous substituents located at the 14-position of the aromathecin system have been proposed to project into the major groove of the top1-DNA complex and hydrogen-bond to major-groove amino acids, thereby stabilizing the ternary complex.
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pubmed:grant |
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pubmed:commentsCorrections |
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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 |
Aug
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pubmed:issn |
1520-4804
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:day |
14
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pubmed:volume |
51
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
4609-19
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pubmed:dateRevised |
2010-11-18
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pubmed:meshHeading |
pubmed-meshheading:18630891-Antineoplastic Agents,
pubmed-meshheading:18630891-Cell Line, Tumor,
pubmed-meshheading:18630891-Cell Proliferation,
pubmed-meshheading:18630891-DNA,
pubmed-meshheading:18630891-DNA Topoisomerases, Type I,
pubmed-meshheading:18630891-Drug Design,
pubmed-meshheading:18630891-Humans,
pubmed-meshheading:18630891-Indolizines,
pubmed-meshheading:18630891-Ligands,
pubmed-meshheading:18630891-Models, Molecular,
pubmed-meshheading:18630891-Molecular Structure,
pubmed-meshheading:18630891-Protein Binding,
pubmed-meshheading:18630891-Quinolines,
pubmed-meshheading:18630891-Structure-Activity Relationship,
pubmed-meshheading:18630891-Topoisomerase I Inhibitors
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pubmed:year |
2008
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pubmed:articleTitle |
Design, synthesis, and biological evaluation of 14-substituted aromathecins as topoisomerase I inhibitors.
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pubmed:affiliation |
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Purdue CancerCenter, Purdue University, West Lafayette, Indiana 47907, USA.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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