Synthesis and structure-activity relationship of 1- and 2-substituted-1,2,3-triazole letrozole-based analogues as aromatase inhibitors

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DOIResolve DOI: http://doi.org/10.1016/j.ejmech.2011.05.074
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TypeArticle
Journal titleEuropean Journal of Medicinal Chemistry
ISSN0223-5234
Volume46
Issue9
Pages40104024; # of pages: 15
Subject1 (4 cyanophenylmethyl) 1h 1,2,3 triazole; 1 (4 cyanophenylmethyl) 1h imidazole; 1 (4,4' dicyanodiphenylmethyl) 1h 1,2,3 triazole; 1 (4,4' dicyanodiphenylmethyl) 1h imidazole; 1 (4,4' dicyanodiphenylmethyl) 4 [(4 cyanophenoxy)methyl] 1h 1,2,3 triazole; 1 (4,4' dicyanodiphenylmethyl) 4 hexyl 1h 1,2,3 triazole; 1 (4,4' dicyanodiphenylmethyl) 4 propyl 1h 1,2,3 triazole; 1 (diphenylmethyl) 1h imidazole; 1 (phenylmethyl) 4 cyano phenoxymethyl 1h 1,2,3 triazole; 1 (phenylmethyl) 4 methyl phenoxymethyl 1h 1,2,3 triazole; 1 (phenylmethyl) 4 nitro phenoxymethyl 1h 1,2,3 triazole; 1,2,3 triazole derivative; 1,2,5 triazole derivative; 2 (4,4' dicyanodiphenylmethyl) 2h 1,2,3 triazole; aromatase inhibitor; letrozole; triazole derivative; unclassified drug; adrenal cortex carcinoma; article; cancer growth; carcinoma cell; controlled study; drug binding; drug inhibition; drug screening; drug structure; drug synthesis; human; human cell; IC 50; in vitro study; structure activity relation; Aromatase Inhibitors; Cell Line, Tumor; Cell Proliferation; Computer Simulation; Humans; Inhibitory Concentration 50; Magnetic Resonance Spectroscopy; Mass Spectrometry; Nitriles; Structure-Activity Relationship; Triazoles
AbstractA series of bis- and mono-benzonitrile or phenyl analogues of letrozole 1, bearing (1,2,3 and 1,2,5)-triazole or imidazole, were synthesized and screened for their anti-aromatase activities. The unsubstituted 1,2,3-triazole 10a derivative displayed inhibitory activity comparable with that of the aromatase inhibitor, letrozole 1. Compound 10a, bearing a 1,2,3-triazole, is also 10000-times more tightly binding than the corresponding analogue 25 bearing a 1,2,5-triazole, which confirms the importance of a nitrogen atom at position 3 or 4 of the 5-membered ring needed for high activity. The effect on human epithelial adrenocortical carcinoma cell line (H295R) proliferation was also evaluated. The compound 10j (IC 50 = 4.64 μM), a letrozole 1 analogue bearing para-cyanophenoxymethylene-1,2,3-triazole decreased proliferation rates of H295R cells by 76 and 99% in 24 and 72 h respectively. Computer calculations, using quantum ab initio structures, suggest a possible correlation between anti-aromatase activity and the distance between the nitrogen in position 3 or 4 of triazole nitrogen and the cyano group nitrogen. © 2011 Elsevier Masson SAS. All rights reserved.
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LanguageEnglish
AffiliationNational Research Council Canada (NRC-CNRC); NRC Institute for Information Technology (IIT-ITI)
Peer reviewedYes
NPARC number21271486
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Record identifier6384f901-e897-4625-b758-e21151a84713
Record created2014-03-24
Record modified2016-05-09
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