Expanding the anticancer potential of 1,2,3-triazoles via simultaneously targeting Cyclooxygenase-2, 15-lipoxygenase and tumor-associated carbonic anhydrases.

Expanding the anticancer potential of 1,2,3-triazoles via simultaneously targeting Cyclooxygenase-2, 15-lipoxygenase and tumor-associated carbonic anhydrases. Eur J Med Chem. 2020 May 25;200:112439 Authors: Elzahhar PA, Abd El Wahab SM, Elagawany M, Daabees H, Belal ASF, El-Yazbi AF, Eid AH, Alaaeddine R, Hegazy RR, Allam RM, Helmy MW, Bahaa Elgendy, Angeli A, El-Hawash SA, Supuran CT Abstract Cancer is a multifactorial disorder involving multiplicity of interrelated signaling pathways and molecular targets. To that end, a multi-target design strategy was adopted to develop some 1,2,3-triazoles hybridized with some pharmacophoric anticancer fragments, as first-in-class simultaneous inhibitors of COX-2, 15-LOX and tumor associated carbonic anhydrase enzymes. Results revealed that compounds 5a, 5d, 8b and 8c were potent inhibitors of COX-2 and 15-LOX enzymes. COX-2 inhibitory activity was further demonstrated by the inhibition of the accumulation of 6-keto-PGF1α, a metabolite of COX-2 products in two cancer cell lines. The sulfonamide bearing derivatives 5d and 8c were effective nanomolar and submicromolar inhibitors of tumor associated hCA XII isoform, respectively. Strong to moderate inhibitory activities were observed in the in vitro antiproliferative assay on lung (A549), liver (HepG2) and breast (MCF7) cancer cell lines (IC50 2.37-28.5 μM) with high safety margins on WI-38 cells. A cytotoxic advantage of CA inhibition was obs...
Source: European Journal of Medicinal Chemistry - Category: Chemistry Authors: Tags: Eur J Med Chem Source Type: research