Document Detail

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.
MedLine Citation:
PMID:  20334421     Owner:  NLM     Status:  MEDLINE    
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.
Jonathan A Stefely; Rahul Palchaudhuri; Patricia A Miller; Rebecca J Peterson; Garrett C Moraski; Paul J Hergenrother; Marvin J Miller
Publication Detail:
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:
Title:  Journal of medicinal chemistry     Volume:  53     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2010 Apr 
Date Detail:
Created Date:  2010-04-15     Completed Date:  2010-05-14     Revised Date:  2014-09-10    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3389-95     Citation Subset:  IM    
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MeSH Terms
Acrylamides / chemical synthesis*,  chemistry,  pharmacology
Cell Division / drug effects
Cell Line, Tumor
Drug Screening Assays, Antitumor
G2 Phase / drug effects
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
R01 AI05419/AI/NIAID NIH HHS; R01 AI054193/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
Reg. No./Substance:
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

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