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Carbonic anhydrase inhibitors: synthesis and inhibition of the human cytosolic isozymes I and II and transmembrane isozymes IX, XII (cancer-associated) and XIV with 4-substituted 3-pyridinesulfonamides.
Eur J Med Chem. 2010 Jun; 45(6):2396-404.EJ

Abstract

A series of novel 4-substituted-3-pyridinesulfonamides (2-27 and 31-33) 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 isozymes CA I and II, and transmembrane isozymes CA IX, XII (cancer-associated) and XIV. Against the human isozymes hCA I, the new compounds showed inhibition constants in the range of 0.078-11.7 microM, against hCA II in the range of 9.9-140 nM, against hCA IX in the range of 4.6-313 nM, against hCA XII in the range of 3.4-21.6 nM, and against hCA XIV in the range of 50.9-160 nM, respectively. Compounds 4, 6, 7, 9, 11-14, 19, 20, 22-24, 26, 27, 31 and 32 showed excellent hCA IX inhibitory efficacy, with inhibition constants of 4.6-12.0 nM, being much more effective as compared to the clinically used sulfonamides AAZ, MZA, EZA, DCP and IND. 4-[N'-(6-chloro-7-cyano-1,1-dioxo-1,4,2-benzodithiazin-3-yl)hydrazino]-3-pyridinesulfonamide (31) is the prominent of the compounds due to its remarkable inhibitory activity toward hCA I (KIs=0.078 microM), hCA IX (KIs=7.2 nM) and hCA XII (KIs=3.4 nM).

Authors+Show Affiliations

Department of Chemical Technology of Drugs, Medical University of Gdańsk, Al. Gen. J. Hallera 107, 80-416 Gdańsk, Poland.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

20202722

Citation

Brzozowski, Zdzisław, et al. "Carbonic Anhydrase Inhibitors: Synthesis and Inhibition of the Human Cytosolic Isozymes I and II and Transmembrane Isozymes IX, XII (cancer-associated) and XIV With 4-substituted 3-pyridinesulfonamides." European Journal of Medicinal Chemistry, vol. 45, no. 6, 2010, pp. 2396-404.
Brzozowski Z, Sławiński J, Saczewski F, et al. Carbonic anhydrase inhibitors: synthesis and inhibition of the human cytosolic isozymes I and II and transmembrane isozymes IX, XII (cancer-associated) and XIV with 4-substituted 3-pyridinesulfonamides. Eur J Med Chem. 2010;45(6):2396-404.
Brzozowski, Z., Sławiński, J., Saczewski, F., Innocenti, A., & Supuran, C. T. (2010). Carbonic anhydrase inhibitors: synthesis and inhibition of the human cytosolic isozymes I and II and transmembrane isozymes IX, XII (cancer-associated) and XIV with 4-substituted 3-pyridinesulfonamides. European Journal of Medicinal Chemistry, 45(6), 2396-404. https://doi.org/10.1016/j.ejmech.2010.02.020
Brzozowski Z, et al. Carbonic Anhydrase Inhibitors: Synthesis and Inhibition of the Human Cytosolic Isozymes I and II and Transmembrane Isozymes IX, XII (cancer-associated) and XIV With 4-substituted 3-pyridinesulfonamides. Eur J Med Chem. 2010;45(6):2396-404. PubMed PMID: 20202722.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Carbonic anhydrase inhibitors: synthesis and inhibition of the human cytosolic isozymes I and II and transmembrane isozymes IX, XII (cancer-associated) and XIV with 4-substituted 3-pyridinesulfonamides. AU - Brzozowski,Zdzisław, AU - Sławiński,Jarosław, AU - Saczewski,Franciszek, AU - Innocenti,Alessio, AU - Supuran,Claudiu T, Y1 - 2010/02/12/ PY - 2009/12/21/received PY - 2010/02/03/revised PY - 2010/02/04/accepted PY - 2010/3/6/entrez PY - 2010/3/6/pubmed PY - 2010/7/28/medline SP - 2396 EP - 404 JF - European journal of medicinal chemistry JO - Eur J Med Chem VL - 45 IS - 6 N2 - A series of novel 4-substituted-3-pyridinesulfonamides (2-27 and 31-33) 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 isozymes CA I and II, and transmembrane isozymes CA IX, XII (cancer-associated) and XIV. Against the human isozymes hCA I, the new compounds showed inhibition constants in the range of 0.078-11.7 microM, against hCA II in the range of 9.9-140 nM, against hCA IX in the range of 4.6-313 nM, against hCA XII in the range of 3.4-21.6 nM, and against hCA XIV in the range of 50.9-160 nM, respectively. Compounds 4, 6, 7, 9, 11-14, 19, 20, 22-24, 26, 27, 31 and 32 showed excellent hCA IX inhibitory efficacy, with inhibition constants of 4.6-12.0 nM, being much more effective as compared to the clinically used sulfonamides AAZ, MZA, EZA, DCP and IND. 4-[N'-(6-chloro-7-cyano-1,1-dioxo-1,4,2-benzodithiazin-3-yl)hydrazino]-3-pyridinesulfonamide (31) is the prominent of the compounds due to its remarkable inhibitory activity toward hCA I (KIs=0.078 microM), hCA IX (KIs=7.2 nM) and hCA XII (KIs=3.4 nM). SN - 1768-3254 UR - https://www.unboundmedicine.com/medline/citation/20202722/Carbonic_anhydrase_inhibitors:_synthesis_and_inhibition_of_the_human_cytosolic_isozymes_I_and_II_and_transmembrane_isozymes_IX_XII__cancer_associated__and_XIV_with_4_substituted_3_pyridinesulfonamides_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0223-5234(10)00137-6 DB - PRIME DP - Unbound Medicine ER -