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Carbonic anhydrase inhibitors. Synthesis of a novel series of 5-substituted 2,4-dichlorobenzenesulfonamides and their inhibition of human cytosolic isozymes I and II and the transmembrane tumor-associated isozymes IX and XII.
Eur J Med Chem. 2014 Jul 23; 82:47-55.EJ

Abstract

A series of novel 5-substituted 2,4-dichlorobenzenesulfonamides 5a-c, 6a-d, 7a-j and 10a-i 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 CA I investigated compounds displayed KI values from 349 to 7355 nM, toward hCA II at range of 6.9 to 164 nM, while against hCA IX ranging from 2.8 to 76 nM and against hCA XII in the range of 2.7 to 95 nM. The excellent inhibitory activity against tumor-associated hCA IX was found. The twenty one new compounds displayed a powerful inhibitory potency toward hCA IX (KI = 2.8-21.7 nM) in comparison with the clinically used CAIs AAZ, MZA, EZA, DCP and IND (24-50 nM). Among them the most potent hCA IX inhibitor 7b (KI = 2.8 nM) was 8.5-fold stronger than IND (KI = 24 nM). Toward tumor-associated hCA XII compounds 6c and 10a (KI = 2.7 and 2.8 nM, respectively) showed a better inhibitory potency than reference sulfonamides MZA and IND (KI = 3.4 nM).

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.Department of Organic Chemistry, Medical University of Gdańsk, Al. Gen. J. Hallera 107, 80-416 Gdańsk, Poland.Department of Organic Chemistry, Medical University of Gdańsk, Al. Gen. J. Hallera 107, 80-416 Gdańsk, Poland.Department of Organic Chemistry, Medical University of Gdańsk, Al. Gen. J. Hallera 107, 80-416 Gdańsk, Poland.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.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.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

24871996

Citation

Sławiński, Jarosław, et al. "Carbonic Anhydrase Inhibitors. Synthesis of a Novel Series of 5-substituted 2,4-dichlorobenzenesulfonamides and Their Inhibition of Human Cytosolic Isozymes I and II and the Transmembrane Tumor-associated Isozymes IX and XII." European Journal of Medicinal Chemistry, vol. 82, 2014, pp. 47-55.
Sławiński J, Pogorzelska A, Żołnowska B, et al. Carbonic anhydrase inhibitors. Synthesis of a novel series of 5-substituted 2,4-dichlorobenzenesulfonamides and their inhibition of human cytosolic isozymes I and II and the transmembrane tumor-associated isozymes IX and XII. Eur J Med Chem. 2014;82:47-55.
Sławiński, J., Pogorzelska, A., Żołnowska, B., Brożewicz, K., Vullo, D., & Supuran, C. T. (2014). Carbonic anhydrase inhibitors. Synthesis of a novel series of 5-substituted 2,4-dichlorobenzenesulfonamides and their inhibition of human cytosolic isozymes I and II and the transmembrane tumor-associated isozymes IX and XII. European Journal of Medicinal Chemistry, 82, 47-55. https://doi.org/10.1016/j.ejmech.2014.05.039
Sławiński J, et al. Carbonic Anhydrase Inhibitors. Synthesis of a Novel Series of 5-substituted 2,4-dichlorobenzenesulfonamides and Their Inhibition of Human Cytosolic Isozymes I and II and the Transmembrane Tumor-associated Isozymes IX and XII. Eur J Med Chem. 2014 Jul 23;82:47-55. PubMed PMID: 24871996.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Carbonic anhydrase inhibitors. Synthesis of a novel series of 5-substituted 2,4-dichlorobenzenesulfonamides and their inhibition of human cytosolic isozymes I and II and the transmembrane tumor-associated isozymes IX and XII. AU - Sławiński,Jarosław, AU - Pogorzelska,Aneta, AU - Żołnowska,Beata, AU - Brożewicz,Kamil, AU - Vullo,Daniela, AU - Supuran,Claudiu T, Y1 - 2014/05/13/ PY - 2013/09/12/received PY - 2013/12/16/revised PY - 2014/05/08/accepted PY - 2014/5/30/entrez PY - 2014/5/30/pubmed PY - 2015/3/31/medline KW - 2,4-Dichlorobenzenesulfonamides KW - Carbonic anhydrase isozymes I, II, IX and XII inhibitors KW - Synthesis SP - 47 EP - 55 JF - European journal of medicinal chemistry JO - Eur J Med Chem VL - 82 N2 - A series of novel 5-substituted 2,4-dichlorobenzenesulfonamides 5a-c, 6a-d, 7a-j and 10a-i 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 CA I investigated compounds displayed KI values from 349 to 7355 nM, toward hCA II at range of 6.9 to 164 nM, while against hCA IX ranging from 2.8 to 76 nM and against hCA XII in the range of 2.7 to 95 nM. The excellent inhibitory activity against tumor-associated hCA IX was found. The twenty one new compounds displayed a powerful inhibitory potency toward hCA IX (KI = 2.8-21.7 nM) in comparison with the clinically used CAIs AAZ, MZA, EZA, DCP and IND (24-50 nM). Among them the most potent hCA IX inhibitor 7b (KI = 2.8 nM) was 8.5-fold stronger than IND (KI = 24 nM). Toward tumor-associated hCA XII compounds 6c and 10a (KI = 2.7 and 2.8 nM, respectively) showed a better inhibitory potency than reference sulfonamides MZA and IND (KI = 3.4 nM). SN - 1768-3254 UR - https://www.unboundmedicine.com/medline/citation/24871996/Carbonic_anhydrase_inhibitors__Synthesis_of_a_novel_series_of_5_substituted_24_dichlorobenzenesulfonamides_and_their_inhibition_of_human_cytosolic_isozymes_I_and_II_and_the_transmembrane_tumor_associated_isozymes_IX_and_XII_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0223-5234(14)00453-X DB - PRIME DP - Unbound Medicine ER -