A series of novel heterocyclic 4-substituted pyridine-3-sulfonamides 2-13, 15-20 have been synthesized and investigated as inhibitors of four isoforms of zinc enzyme carbonic anhydrase (CA.EC 4.2.1.1), that is the cytosolic CA I and II, and tumor-associated isozymes CA IX and XII. Against the human isozymes hCA I the new compounds showed K(I) values in the range 169-5400 nM, toward hCA II in range 58.5-1238 nM, against hCA IX in range 19.5-652 nM and against hCA XII in the range of 16.8-768 nM. Compounds 15-19 representing 4-(1H-pyrazol-1-yl)-3-pyridinesulfonamide derivatives showed good hCA IX inhibitory efficacy with K(I) = 19.5-48.6 nM comparable or more effective than clinically used sulfonamides: AAZ, MZA, EZA, DCP, IND (K(I) = 24-50 nM). Anticancer evaluation at a single dose 10 μM, against a panel of 60 human tumor cell lines, was performed at the US National Cancer Institute, on compounds 2, 3, 5-13, 16, 17, 19, 20. Among them 6 bearing 4-(3,4,-dichlorophenyl)piperazine moiety showed broad spectrum of growth inhibition in the range 25-89% over 26 cell lines representing all tumors subpanels.
Carbonic anhydrase inhibitors. Synthesis of heterocyclic 4-substituted pyridine-3-sulfonamide derivatives and their inhibition of the human cytosolic isozymes i and II and transmembrane tumor-associated isozymes IX and XII / Sławiński, Jarosław; Szafrański, Krzysztof; Vullo, Daniela; Supuran, Claudiu T.. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - STAMPA. - 69:(2013), pp. 701-710. [10.1016/j.ejmech.2013.09.027]
Carbonic anhydrase inhibitors. Synthesis of heterocyclic 4-substituted pyridine-3-sulfonamide derivatives and their inhibition of the human cytosolic isozymes i and II and transmembrane tumor-associated isozymes IX and XII
VULLO, DANIELA;SUPURAN, CLAUDIU TRANDAFIR
2013
Abstract
A series of novel heterocyclic 4-substituted pyridine-3-sulfonamides 2-13, 15-20 have been synthesized and investigated as inhibitors of four isoforms of zinc enzyme carbonic anhydrase (CA.EC 4.2.1.1), that is the cytosolic CA I and II, and tumor-associated isozymes CA IX and XII. Against the human isozymes hCA I the new compounds showed K(I) values in the range 169-5400 nM, toward hCA II in range 58.5-1238 nM, against hCA IX in range 19.5-652 nM and against hCA XII in the range of 16.8-768 nM. Compounds 15-19 representing 4-(1H-pyrazol-1-yl)-3-pyridinesulfonamide derivatives showed good hCA IX inhibitory efficacy with K(I) = 19.5-48.6 nM comparable or more effective than clinically used sulfonamides: AAZ, MZA, EZA, DCP, IND (K(I) = 24-50 nM). Anticancer evaluation at a single dose 10 μM, against a panel of 60 human tumor cell lines, was performed at the US National Cancer Institute, on compounds 2, 3, 5-13, 16, 17, 19, 20. Among them 6 bearing 4-(3,4,-dichlorophenyl)piperazine moiety showed broad spectrum of growth inhibition in the range 25-89% over 26 cell lines representing all tumors subpanels.I documenti in FLORE sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.