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Carbonic anhydrase inhibitors. Synthesis, molecular structures, and inhibition of the human cytosolic isozymes I and II and transmembrane isozymes IX, XII (cancer-associated) and XIV with novel 3-pyridinesulfonamide derivatives |
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| Authors: | Brzozowski Zdzisław Sławiński Jarosław Gdaniec Maria Innocenti Alessio Supuran Claudiu T |
| Institution: | a Department of Organic Chemistry, Medical University of Gdańsk, Al. Gen. J. Hallera 107, 80-416 Gdańsk, Poland b Faculty of Chemistry, A. Mickiewicz University, 60-780 Poznań, Poland c Dipartimento di Chimica, Universita degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy |
| Abstract: | A series of novel 3-pyridinesulfonamide derivatives (2-5, 9-11 and 13-15) have been synthesized and investigated as inhibitors of five isoforms of zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), that is, the cytosolic ubiquitous CA I and II, and isozymes CA IX and XII (cancer-associated), and XIV. Against the human isozyme hCA I the new compounds showed KIs in the range of 0.089-251 μM, whereas toward hCA II, KIs = 50.5-487 nM. Isozyme hCA IX was inhibited with KIs in the range of 5.2-18.3 nM, while hCA XII with KIs = 6.0-16.4 nM, and hCA XIV with KIs = 76.4-152.0 nM. All of the new compounds 2-5, 9-11 and 13-15 showed excellent hCA IX inhibitory efficacy, with KIs = 5.2-18.3 nM, being much more effective as compared to the clinically used AAZ, MZA, EZA, DCP and IND (KIs = 24-50 nM). |
| Keywords: | 3-Pyridinesulfonamides Synthesis X-ray structure Carbonic anhydrase isozymes I II IX XII and XIV inhibitors |
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