title: Synthesis and structure-activity relationship of 1- and 2-substituted-1,2,3-triazole letrozole-based analogues as aromatase inhibitors.
abstract: A 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.
authors.affiliation: Department of Chemistry and Biochemistry, Université de Moncton, Moncton, NB, Canada.
authors.forename: Jérémie
authors.initials: J
authors.lastname: Doiron
authors.forename: Al Haliffa
authors.initials: AH
authors.lastname: Soultan
authors.forename: Ryan
authors.initials: R
authors.lastname: Richard
authors.forename: Mamadou Mansour
authors.initials: MM
authors.lastname: Touré
authors.forename: Nadia
authors.initials: N
authors.lastname: Picot
authors.forename: Rémi
authors.initials: R
authors.lastname: Richard
authors.forename: Miroslava
authors.initials: M
authors.lastname: Cuperlović-Culf
authors.forename: Gilles A
authors.initials: GA
authors.lastname: Robichaud
authors.forename: Mohamed
authors.initials: M
authors.lastname: Touaibia
mesh_terms: D047072:Aromatase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003198:Computer Simulation; D006801:Humans; D020128:Inhibitory Concentration 50; D000077289:Letrozole; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D047072:Aromatase Inhibitors; D009570:Nitriles; D014230:Triazoles; D000077289:Letrozole