Expanding the anticancer potential of 1,2,3-triazoles via simultaneously targeting Cyclooxygenase-2, 15-lipoxygenase and tumor-associated carbonic anhydrases
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Elsevier Masson SAS
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 observed as an increased activity against tumor cell lines expressing CA IX/XII. Further mechanistic clues for the anticancer activities of compound 5a and its sulfonamide analog 5d were derived from induction of cell cycle arrest at G2/M phase. They also triggered apoptosis via increasing expression levels of caspase-9 and Bax together with suppressing that of Bcl-2. The in vitro anti-tumor activity was reflected as reduced tumor size upon treatment with 8c in an in vivo cancer xenograft model. Docking experiments on the target enzymes supported their in vitro data and served as further molecular evidence. In silico calculations and ligand efficiency indices were promising. In light of these data, such series could offer new structural insights into the understanding and development of multi-target COX-2/15-LOX/hCA inhibitors for anticancer outcomes. © 2020 Elsevier Masson SAS
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1,2,3-triazoles, 15-lipoxygenase, Apoptosis, Cancer, Carbonic anhydrase, Cyclooxygenase-2, Mtdl, Antineoplastic agents, Arachidonate 15-lipoxygenase, Carbonic anhydrases, Cell proliferation, Cells, cultured, Cyclooxygenase 2, Dose-response relationship, drug, Drug screening assays, antitumor, Enzyme inhibitors, Humans, Molecular structure, Structure-activity relationship, Triazoles, 1,2,3 triazole derivative, 2 [1 [1 (4 chlorophenyl) 5 methyl 1h 1,2,3 triazol 4 yl]ethylidene]hydrazine 1 carboxamide, 2 [1 [1 (4 fluorophenyl) 5 methyl 1h 1,2,3 triazol 4 yl]ethylidene]hydrazine 1 carbothioamide, 2 [1 [1 (4 fluorophenyl) 5 methyl 1h 1,2,3 triazol 4 yl]ethylidene]hydrazine 1 carboxamide, 2 [1 [5 methyl 1 (4 sulfamoylphenyl) 1h 1,2,3 triazol 4 yl]ethylidene]hydrazine 1 carbothioamide, 2 [1 [5 methyl 1 (4 sulfamoylphenyl) 1h 1,2,3 triazol 4 yl]ethylidene]hydrazine 1 carboxamide, 2 [1 [5 methyl 1 [4 [n (thiazol 2 yl)sulfamoyl]phenyl] 1h 1,2,3 triazol 4 yl]ethylidene]hydrazine 1 carbothioamide, 2 [1 [5 methyl 1 [4 [n (thiazol 2 yl)sulfamoyl]phenyl] 1h 1,2,3 triazol 4 yl]ethylidene]hydrazine 1 carboxamide, 3 [1 (4 chlorophenyl) 5 methyl 1h 1,2,3 triazol 4 yl] 1 phenyl 1h pyrazole 4 carbaldehyde oxime, 3 [1 (4 fluorophenyl) 5 methyl 1h 1,2,3 triazol 4 yl] 1 phenyl 1h pyrazole 4 carbaldehyde oxime, 4 (4 acetyl 5 methyl 1h 1,2,3 triazol 1 yl) n (thiazol 2 yl)benzenesulfonamide, 4 (4 acetyl 5 methyl 1h 1,2,3 triazol 1 yl)benzenesulfonamide, 4 (4 acetyl 5 methyl 1h 1,2,3 triazol 1 yl)benzoic acid, 4 (4 chlorophenyl) 2 [2 [1 [1 (4 chlorophenyl) 5 methyl 1h 1,2,3 triazol 4 yl]ethylidene]hydrazineyl]thiazole, 4 (4 chlorophenyl) 2 [2 [1 [1 (4 fluorophenyl) 5 methyl 1h 1,2,3 triazol 4 yl]ethylidene]hydrazineyl]thiazole, 4 [4 [1 (2 carbamothioylhydrazineylidene)ethyl] 5 methyl 1h 1,2,3 triazol 1 yl]benzoic acid, 4 [4 [1 (2 carbamoylhydrazineylidene)ethyl] 5 methyl 1h 1,2,3 triazol 1 yl]benzoic acid, 4 [4 [1 [2 [4 (4 chlorophenyl)thiazol 2 yl]hydrazineylidene]ethyl] 5 methyl 1h 1,2,3 triazol 1 yl] n (thiazol 2 yl)benzenesulfonamide, 4 [4 [1 [2 [4 (4 chlorophenyl)thiazol 2 yl]hydrazineylidene]ethyl] 5 methyl 1h 1,2,3 triazol 1 yl]benzenesulfonamide, 4 [4 [1 [2 [4 (4 chlorophenyl)thiazol 2 yl]hydrazineylidene]ethyl] 5 methyl 1h 1,2,3 triazol 1 yl]benzoic acid, 4 [4 [4 [(hydroxyimino)methyl] 1 phenyl 1h pyrazol 3 yl] 5 methyl 1h 1,2,3 triazol 1 yl]benzenesulfonamide, 4 [4 [4 [(hydroxyimino)methyl] 1 phenyl 1h pyrazol 3 yl] 5 methyl 1h 1,2,3 triazol 1 yl]benzenesulfonic acid, Arachidonate 15 lipoxygenase, Carbonate dehydratase, Carbonate dehydratase inhibitor, Cyclooxygenase 2 inhibitor, Cytotoxic agent, Lipoxygenase inhibitor, Unclassified drug, Unindexed drug, Antineoplastic agent, Enzyme inhibitor, Triazole derivative, A-549 cell line, Animal experiment, Animal model, Animal tissue, Antineoplastic activity, Antiproliferative activity, Article, Breast cancer, Computer model, Controlled study, Drug design, Drug synthesis, Drug targeting, Enzyme activity, Enzyme inhibition, G2 phase cell cycle checkpoint, Hep-g2 cell line, Human, Human cell, Ic50, In vitro study, In vivo study, Mcf-7 cell line, Mouse, Newborn, Nonhuman, Tumor xenograft, Wi-38 cell line, Cell culture, Chemical structure, Chemistry, Dose response, Drug effect, Drug screening, Metabolism, Structure activity relation, Synthesis