Inhibition of human carbonic anhydrase (hCA) isoform IX with concurrent induction of apoptosis is a promising approach for targeting cancer in humans. Prompted by the scope, novel benzenesulfonamides containing the 1,2,3-triazolylthiazolotriazole tail were synthesized and screened as inhibitors of hCA isoforms I, II, IV, and IX. The tumor-associated isoform hCA IX was strongly inhibited by the sulfonamides reported here with K-I values ranging from 45 nM to 1.882 mu M. Overall, nine compounds showed hCA IX inhibition with K-I < 250 nM. The glaucoma-associated isoform hCA II was moderately inhibited while the cytosolic isoform hCA I and membrane-bound isoform hCA IV were weakly inhibited by the synthesized sulfonamides. Compound 6Ac (K-I = 3.6 nM) was found to be an almost three times more potent inhibitor of hCA II as compared to the standard drug acetazolamide (K-I = 12.1 nM). The selective hCA IX inhibitors were further studied for their apoptotic efficacy in goat ovarian cells and showed better results as compared to the control. A comparative study of previously synthesized compounds and molecular docking study of representative compounds revealed some important generalizations that could prove beneficial in further investigations of isoform-selective hCA inhibitors.
Tail approach synthesis of triazolylthiazolotriazole bearing benzenesulfonamides as carbonic anhydrase inhibitors capable of inducing apoptosis / Vats, Lalit; Siwach, Kiran; Angeli, Andrea; Bikal, Prerna; Bhardwaj, Jitender Kumar; Supuran, Claudiu T; Sharma, Pawan K. - In: ARCHIV DER PHARMAZIE. - ISSN 0365-6233. - ELETTRONICO. - 356:(2023), pp. 0-0. [10.1002/ardp.202200439]
Tail approach synthesis of triazolylthiazolotriazole bearing benzenesulfonamides as carbonic anhydrase inhibitors capable of inducing apoptosis
Angeli, Andrea;Supuran, Claudiu T;
2023
Abstract
Inhibition of human carbonic anhydrase (hCA) isoform IX with concurrent induction of apoptosis is a promising approach for targeting cancer in humans. Prompted by the scope, novel benzenesulfonamides containing the 1,2,3-triazolylthiazolotriazole tail were synthesized and screened as inhibitors of hCA isoforms I, II, IV, and IX. The tumor-associated isoform hCA IX was strongly inhibited by the sulfonamides reported here with K-I values ranging from 45 nM to 1.882 mu M. Overall, nine compounds showed hCA IX inhibition with K-I < 250 nM. The glaucoma-associated isoform hCA II was moderately inhibited while the cytosolic isoform hCA I and membrane-bound isoform hCA IV were weakly inhibited by the synthesized sulfonamides. Compound 6Ac (K-I = 3.6 nM) was found to be an almost three times more potent inhibitor of hCA II as compared to the standard drug acetazolamide (K-I = 12.1 nM). The selective hCA IX inhibitors were further studied for their apoptotic efficacy in goat ovarian cells and showed better results as compared to the control. A comparative study of previously synthesized compounds and molecular docking study of representative compounds revealed some important generalizations that could prove beneficial in further investigations of isoform-selective hCA inhibitors.I documenti in FLORE sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.