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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.
Eur J Med Chem. 2013 Nov; 69:701-10.EJ

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.

Authors+Show Affiliations

Department of Organic Chemistry, Medical University of Gdańsk, Al. Gen. J. Hallera 107, 80-416 Gdańsk, Poland. Electronic address: jaroslaw@gumed.edu.pl.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

24095761

Citation

Sławiński, Jarosław, et al. "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." European Journal of Medicinal Chemistry, vol. 69, 2013, pp. 701-10.
Sławiński J, Szafrański K, Vullo D, et al. 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. Eur J Med Chem. 2013;69:701-10.
Sławiński, J., Szafrański, K., Vullo, D., & Supuran, C. T. (2013). 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. European Journal of Medicinal Chemistry, 69, 701-10. https://doi.org/10.1016/j.ejmech.2013.09.027
Sławiński J, et al. 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. Eur J Med Chem. 2013;69:701-10. PubMed PMID: 24095761.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Sławiński,Jarosław, AU - Szafrański,Krzysztof, AU - Vullo,Daniela, AU - Supuran,Claudiu T, Y1 - 2013/09/20/ PY - 2013/05/24/received PY - 2013/09/05/revised PY - 2013/09/07/accepted PY - 2013/10/8/entrez PY - 2013/10/8/pubmed PY - 2014/7/9/medline KW - Antitumor activity KW - Carbonic anhydrase isozymes I, II, IX and XII inhibitors KW - Pyridine-3-sulfonamides KW - Synthesis SP - 701 EP - 10 JF - European journal of medicinal chemistry JO - Eur J Med Chem VL - 69 N2 - 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. SN - 1768-3254 UR - https://www.unboundmedicine.com/medline/citation/24095761/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_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0223-5234(13)00600-4 DB - PRIME DP - Unbound Medicine ER -