Περίληψη:
The fusion of 1,2,4-triazole and 1,3,4-thiadiazole rings results in a class of heterocycles compounds with an extensive range of pharmacological properties. A series of 1,2,4-triazolo[3,4-b]-1,2,4-thiadiazoles was synthesized and tested for its enzyme inhibition potential and anticancer activity. The results show that 1,2,4-triazolo[3,4-b]-1,2,4-thiadiazoles display potent anticancer properties in vitro against a panel of cancer cells and in vivo efficacy in HT-29 human colon tumor xenograft in CB17 severe combined immunodeficient (SCID) mice. Preliminary mechanistic studies revealed that KA25 and KA39 exhibit time-and concentration-dependent inhibition of Akt Ser-473 phosphorylation. Molecular modeling experiments indicated that 1,2,4-triazolo[3,4-b]-1,2,4-thiadiazoles bind well to the ATP binding site in Akt1 and Akt2. The low acute toxicity combined with in vitro and in vivo anticancer activity render triazolo[3,4-b]thiadiazoles KA25, KA26, and KA39 promising cancer therapeutic agents. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
Λέξεις-κλειδιά:
2 [(6 (3 chlorophenyl) [1,2,4]triazolo[3,4 b][1,3,4]thiadiazol 3 yl)methyl] n,n diethyl 4,5 dimethoxybenzenesulfonamide; 2 [(6 (3 chlorophenyl) [1,2,4]triazolo[3,4 b][1,3,4]thiadiazol 3 yl)methyl] n,n diisopropyl 4,5 dimethoxybenzenesulfonamide; 2 [(6 (4 chlorophenyl) [1,2,4]triazolo[3,4 b][1,3,4]thiadiazol 3 yl)methyl] n,n diethyl 4,5 dimethoxybenzenesulfonamide; 2 [(6 (4 chlorostyryl) [1,2,4]triazolo[3,4 b][1,3,4]thiadiazol 3 yl)methyl] n,n diethyl 4,5 dimethoxybenzenesulfonamide; 2 [(6 (4 chlorostyryl) [1,2,4]triazolo[3,4 b][1,3,4]thiadiazol 3 yl)methyl] n,n diisopropyl 4,5 dimethoxybenzenesulfonamide; 2 [(6 (4 fluorophenyl) [1,2,4]triazolo[3,4 b][1,3,4]thiadiazol 3 yl)methyl] n,n diisopropyl 4,5 dimethoxybenzenesulfonamide; 2 [(6 (4 fluorostyryl) [1,2,4]triazolo[3,4 b][1,3,4]thiadiazol 3 yl)methyl] n,n diisopropyl 4,5 dimethoxybenzenesulfonamide; antineoplastic agent; n,n diethyl 2 [(6 (4 fluorophenyl) [1,2,4]triazolo[3,4 b][1,3,4]thiadiazol 3 yl)methyl] 4,5 dimethoxybenzenesulfonamide; n,n diethyl 2 [(6 (4 fluorostyryl) [1,2,4]triazolo[3,4 b][1,3,4]thiadiazol 3 yl)methyl] 4,5 dimethoxybenzenesulfonamide; n,n diethyl 4,5 dimethoxy 2 [(6 (3 nitrostyryl) [1,2,4]triazolo[3,4 b][1,3,4]thiadiazol 3 yl)methyl]dimethoxybenzenesulfonamide; n,n diethyl 4,5 dimethoxy 2 [(6 (4 nitrophenyl) [1,2,4]triazolo[3,4 b][1,3,4]thiadiazol 3 yl)methyl]benzenesulfonamide; n,n diethyl 4,5 dimethoxy 2 [(6 (4 nitrostyryl) [1,2,4]triazolo[3,4 b][1,3,4]thiadiazol 3 yl)methyl]dimethoxybenzenesulfonamide; n,n diisopropyl 4,5 dimethoxy 2 [(6 (4 nitrophenyl) [1,2,4]triazolo[3,4 b][1,3,4]thiadiazol 3 yl)methyl]benzenesulfonamide; protein kinase B; protein kinase B beta; unclassified drug, animal experiment; animal model; antineoplastic activity; antiproliferative activity; Article; binding site; carbon nuclear magnetic resonance; cell viability; controlled study; drug determination; drug effect; enzyme activation; enzyme inhibition; enzyme phosphorylation; female; human; human cell; IC50; in vitro study; in vivo study; male; molecular docking; molecular model; mouse; MTT assay; nonhuman; tumor xenograft
