| N-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)arylamide as a new scaffold that provides rapid access to antimicrotubule agents: synthesis and evaluation of antiproliferative activity against select cancer cell lines. | |
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MedLine Citation:
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PMID: 20334421 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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A series of N-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)arylamides was synthesized by copper-catalyzed azide-alkyne cycloaddition (CuAAC) and afforded inhibitors of cancer cell growth. For example, compound 13e had an IC(50) of 46 nM against MCF-7 human breast tumor cells. Structure-activity relationship (SAR) studies demonstrated that (i) meta-phenoxy substitution of the N-1-benzyl group is important for antiproliferative activity and (ii) a variety of heterocyclic substitutions for the aryl group of the arylamide are tolerated. In silico COMPARE analysis of antiproliferative activity against the NCI-60 human tumor cell line panel revealed a correlation to clinically useful antimicrotubule agents such as paclitaxel and vincristine. This in silico correlation was supported by (i) in vitro inhibition of tubulin polymerization, (ii) G(2)/M-phase arrest in HeLa cells as assessed by flow cytometry, and (iii) perturbation of normal microtubule activity in HeLa cells as observed by confocal microscopy. The results demonstrate that N-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)arylamide is a readily accessible small molecule scaffold for compounds that inhibit tubulin polymerization and tumor cell growth. |
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Authors:
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Jonathan A Stefely; Rahul Palchaudhuri; Patricia A Miller; Rebecca J Peterson; Garrett C Moraski; Paul J Hergenrother; Marvin J Miller |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. |
Journal Detail:
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Title: Journal of medicinal chemistry Volume: 53 ISSN: 1520-4804 ISO Abbreviation: J. Med. Chem. Publication Date: 2010 Apr |
Date Detail:
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Created Date: 2010-04-15 Completed Date: 2010-05-14 Revised Date: 2013-04-12 |
Medline Journal Info:
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Nlm Unique ID: 9716531 Medline TA: J Med Chem Country: United States |
Other Details:
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Languages: eng Pagination: 3389-95 Citation Subset: IM |
Affiliation:
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Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Acrylamides
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chemical synthesis*,
chemistry,
pharmacology Cell Division / drug effects Cell Line, Tumor Drug Screening Assays, Antitumor G2 Phase / drug effects Humans Microtubules / drug effects, ultrastructure Oxazoles / chemical synthesis*, chemistry, pharmacology Structure-Activity Relationship Triazoles / chemical synthesis*, chemistry, pharmacology Tubulin / chemistry Tubulin Modulators / chemical synthesis*, chemistry, pharmacology |
| Grant Support | |
ID/Acronym/Agency:
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R01 AI05419/AI/NIAID NIH HHS; R01 AI054193-01A2/AI/NIAID NIH HHS; R01 AI054193-02/AI/NIAID NIH HHS; R01 AI054193-03/AI/NIAID NIH HHS; R01 AI054193-04/AI/NIAID NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/2-(4-methoxyphenyl)-N-((1-(3-phenoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)oxazole-4-carboxamide; 0/Acrylamides; 0/Oxazoles; 0/Triazoles; 0/Tubulin; 0/Tubulin Modulators |
| Comments/Corrections | |
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