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Synthesis of a new series of N⁴-substituted 4-(2-aminoethyl)benzenesulfonamides and their inhibitory effect on human carbonic anhydrase cytosolic isozymes I and II and transmembrane tumor-associated isozymes IX and XII.
Eur J Med Chem. 2014 Sep 12; 84:59-67.EJ

Abstract

A series of novel N(4)-substituted 4-(2-aminoethyl)benzenesulfonamides 5-17 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 96.3 to 3520 nM, toward hCA II at range of 18.1-2055 nM, while against hCA IX ranging from 5.9 to 419 nM and against hCA XII in the range of 4.0-414 nM. The very good inhibitory activity against tumor-associated hCA IX and hCA XII was found. The six new compounds displayed a powerful inhibitory potency toward hCA IX (K(I) = 5.9-10.7 nM) in comparison with the clinically used CAIs AAZ, MZA, EZA, DCP and IND (24-50 nM). The most potent hCA IX and hCA XII inhibitors 11 and 12 (K(I): 5.9 and 6.2 nM for hCA IX and 4.3 and 4.0 nM for hCA XII, respectively) belonged to the compounds with cationic character and presented meaningful affinity to the transmembrane isoforms hCA IX and XII than to physiologically dominant isozymes hCA I and II with the selectivity ratios hCA IX versus hCA II and hCA XII versus hCA II for 11 and 12 in the range of 10-15.

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.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

25016228

Citation

Sławiński, Jarosław, et al. "Synthesis of a New Series of N⁴-substituted 4-(2-aminoethyl)benzenesulfonamides and Their Inhibitory Effect On Human Carbonic Anhydrase Cytosolic Isozymes I and II and Transmembrane Tumor-associated Isozymes IX and XII." European Journal of Medicinal Chemistry, vol. 84, 2014, pp. 59-67.
Sławiński J, Brzozowski Z, Żołnowska B, et al. Synthesis of a new series of N⁴-substituted 4-(2-aminoethyl)benzenesulfonamides and their inhibitory effect on human carbonic anhydrase cytosolic isozymes I and II and transmembrane tumor-associated isozymes IX and XII. Eur J Med Chem. 2014;84:59-67.
Sławiński, J., Brzozowski, Z., Żołnowska, B., Szafrański, K., Pogorzelska, A., Vullo, D., & Supuran, C. T. (2014). Synthesis of a new series of N⁴-substituted 4-(2-aminoethyl)benzenesulfonamides and their inhibitory effect on human carbonic anhydrase cytosolic isozymes I and II and transmembrane tumor-associated isozymes IX and XII. European Journal of Medicinal Chemistry, 84, 59-67. https://doi.org/10.1016/j.ejmech.2014.06.074
Sławiński J, et al. Synthesis of a New Series of N⁴-substituted 4-(2-aminoethyl)benzenesulfonamides and Their Inhibitory Effect On Human Carbonic Anhydrase Cytosolic Isozymes I and II and Transmembrane Tumor-associated Isozymes IX and XII. Eur J Med Chem. 2014 Sep 12;84:59-67. PubMed PMID: 25016228.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Synthesis of a new series of N⁴-substituted 4-(2-aminoethyl)benzenesulfonamides and their inhibitory effect on human carbonic anhydrase cytosolic isozymes I and II and transmembrane tumor-associated isozymes IX and XII. AU - Sławiński,Jarosław, AU - Brzozowski,Zdzisław, AU - Żołnowska,Beata, AU - Szafrański,Krzysztof, AU - Pogorzelska,Aneta, AU - Vullo,Daniela, AU - Supuran,Claudiu T, Y1 - 2014/07/05/ PY - 2013/12/09/received PY - 2014/06/29/accepted PY - 2014/7/13/entrez PY - 2014/7/13/pubmed PY - 2015/4/18/medline KW - Carbonic anhydrase isozymes I, II, IX and XII inhibitors KW - Sulfonamide KW - Synthesis SP - 59 EP - 67 JF - European journal of medicinal chemistry JO - Eur J Med Chem VL - 84 N2 - A series of novel N(4)-substituted 4-(2-aminoethyl)benzenesulfonamides 5-17 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 96.3 to 3520 nM, toward hCA II at range of 18.1-2055 nM, while against hCA IX ranging from 5.9 to 419 nM and against hCA XII in the range of 4.0-414 nM. The very good inhibitory activity against tumor-associated hCA IX and hCA XII was found. The six new compounds displayed a powerful inhibitory potency toward hCA IX (K(I) = 5.9-10.7 nM) in comparison with the clinically used CAIs AAZ, MZA, EZA, DCP and IND (24-50 nM). The most potent hCA IX and hCA XII inhibitors 11 and 12 (K(I): 5.9 and 6.2 nM for hCA IX and 4.3 and 4.0 nM for hCA XII, respectively) belonged to the compounds with cationic character and presented meaningful affinity to the transmembrane isoforms hCA IX and XII than to physiologically dominant isozymes hCA I and II with the selectivity ratios hCA IX versus hCA II and hCA XII versus hCA II for 11 and 12 in the range of 10-15. SN - 1768-3254 UR - https://www.unboundmedicine.com/medline/citation/25016228/Synthesis_of_a_new_series_of_N⁴_substituted_4__2_aminoethyl_benzenesulfonamides_and_their_inhibitory_effect_on_human_carbonic_anhydrase_cytosolic_isozymes_I_and_II_and_transmembrane_tumor_associated_isozymes_IX_and_XII_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0223-5234(14)00603-5 DB - PRIME DP - Unbound Medicine ER -