Synthesis and cyclooxygenase inhibition of various (aryl-1,2,3-triazole-1-yl)-methanesulfonylphenyl derivatives.
A series of 1,4- and 1,5-diaryl substituted 1,2,3-triazoles was synthesized by either Cu(I)-catalyzed or Ru(II)-catalyzed 1,3-dipolar cycloaddition reactions between 1-azido-4-methane-sulfonylbenzene 9 and a panel of various para-substituted phenyl acetylenes (4-H, 4-Me, 4-OMe, 4-NMe(2), 4-Cl, 4-F). All compounds were used in in vitro cyclooxygenase (COX) assays to determine the combined electronic and steric effects upon COX-1 and COX-2 inhibitory potency and selectivity. Structure-activity relationship studies showed that compounds having a vicinal diaryl substitution pattern showed more potent COX-2 inhibition (IC(50)=0.03-0.36 microM) compared to their corresponding 1,3-diaryl-substituted counterparts (IC(50)=0.15 to >10.0 microM). In both series, compounds possessing an electron-withdrawing group (Cl and F) at the para-position of one of the aryl rings displayed higher COX-2 inhibition potency and selectivity as determined for compounds containing electron-donating groups (Me, OMe, NMe(2)). The obtained data show, that the central carbocyclic or heterocyclic ring system as found in many COX-2 inhibitors can be replaced by a central 1,2,3-triazole unit without losing COX-2 inhibition potency and selectivity. The high COX-2 inhibition potency of some 1,2,3-triazoles having a vicinal diaryl substitution pattern along with their ease in synthesis through versatile Ru(II)-catalyzed click chemistry make this class of compounds interesting candidates for further design and synthesis of highly selective and potent COX-2 inhibitors.
Wuest
Frank
F
Department of Oncology, University of Alberta, Edmonton, Canada. frankwue@cancerboard.ab.ca
Tang
Xinli
X
Kniess
Torsten
T
Pietzsch
Jens
J
Suresh
Mavanur
M
D002384:Catalysis; D003300:Copper / Q000737:chemistry; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D012428:Ruthenium / Q000737:chemistry; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D016861:Cyclooxygenase Inhibitors; D014230:Triazoles; D003300:Copper; D012428:Ruthenium