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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
1
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pubmed:dateCreated |
2011-9-15
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pubmed:abstractText |
The synthesis and optimization of a series of orally bioavailable 1-(1H-indol-4-yl)-3,5-disubstituted benzene analogues as antimitotic agents are described. A functionalized dibromobenzene intermediate was used as a key scaffold, which when modified by sequential Suzuki coupling and Buchwald-Hartwig amination provided a flexible entry to 1,3,5-trisubstituted phenyl compounds. A 1H-indol-4-yl moiety at the 1-position was determined to be a critical feature for optimal potency. The compounds have been shown to induce cell cycle arrest at the G2/M phase and demonstrate efficacy in both cell viability and cell proliferation assays. The primary site of action for these agents is revealed by their colchicine competitive inhibition of tubulin polymerization, and a computational model has been developed for the association of these compounds to tubulin. An optimized lead LP-261 significantly inhibits growth of a human non-small-cell lung tumor (NCI-H522) in a mouse xenograft model.
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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 |
Jan
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pubmed:issn |
1520-4804
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pubmed:author |
pubmed-author:BukhtiyarovaMarinaM,
pubmed-author:ChaoWenchunW,
pubmed-author:DorseyBruce DBD,
pubmed-author:FlubacherDietmarD,
pubmed-author:FlynnGary AGA,
pubmed-author:FujimotoTedT,
pubmed-author:HusainArifaA,
pubmed-author:JosephRhoda WRW,
pubmed-author:KellyMartha JMJ,
pubmed-author:LeeKyoung-JinKJ,
pubmed-author:LeeYoungheeY,
pubmed-author:LiuBinB,
pubmed-author:LuYixinY,
pubmed-author:MihelcicJohnJ,
pubmed-author:MoffettKristofer KKK,
pubmed-author:MooreWilliam RWR,
pubmed-author:NelsonDavidD,
pubmed-author:OchmanAlexander RAR,
pubmed-author:SaporitoMichael SMS,
pubmed-author:SchumacherAndreasA,
pubmed-author:ShettyRupa SRS,
pubmed-author:SpringmanEric BEB,
pubmed-author:StojanovicAleksandarA,
pubmed-author:WilliamsKenK
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pubmed:issnType |
Electronic
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pubmed:day |
13
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pubmed:volume |
54
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
179-200
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pubmed:meshHeading |
pubmed-meshheading:21126027-Animals,
pubmed-meshheading:21126027-Biological Availability,
pubmed-meshheading:21126027-Cell Line, Tumor,
pubmed-meshheading:21126027-Cell Proliferation,
pubmed-meshheading:21126027-Cell Survival,
pubmed-meshheading:21126027-Colchicine,
pubmed-meshheading:21126027-Drug Screening Assays, Antitumor,
pubmed-meshheading:21126027-G2 Phase,
pubmed-meshheading:21126027-Humans,
pubmed-meshheading:21126027-Indoles,
pubmed-meshheading:21126027-Isonicotinic Acids,
pubmed-meshheading:21126027-Mice,
pubmed-meshheading:21126027-Mice, Nude,
pubmed-meshheading:21126027-Models, Molecular,
pubmed-meshheading:21126027-Neoplasm Transplantation,
pubmed-meshheading:21126027-Rats,
pubmed-meshheading:21126027-Rats, Sprague-Dawley,
pubmed-meshheading:21126027-Structure-Activity Relationship,
pubmed-meshheading:21126027-Sulfonamides,
pubmed-meshheading:21126027-Transplantation, Heterologous,
pubmed-meshheading:21126027-Tubulin,
pubmed-meshheading:21126027-Tubulin Modulators
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pubmed:year |
2011
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pubmed:articleTitle |
Synthesis and pharmacological evaluation of N-(3-(1H-indol-4-yl)-5-(2-methoxyisonicotinoyl)phenyl)methanesulfonamide (LP-261), a potent antimitotic agent.
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pubmed:affiliation |
Ansaris, Four Valley Square, Blue Bell, Pennsylvania 19401, United States. rshetty@ansarisbio.com
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pubmed:publicationType |
Journal Article
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