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Carbonic anhydrase inhibitors. Regioselective synthesis of novel series 1-substituted 1,4-dihydro-4-oxo-3-pyridinesulfonamides and their inhibition of the human cytosolic isozymes I and II and transmembrane cancer-associated isozymes IX and XII.
Eur J Med Chem. 2012 Oct; 56:282-91.EJ

Abstract

A series of novel 1-substituted 1,4-dihydro-4-oxo-3-pyridinesulfonamides 4-6, 9-17 and 21-31 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 cancer-associated isozymes CA IX and XII. Against the human isozymes hCA I the new compounds showed K(I)s in the range of 224-4830 nM, whereas toward hCA II, K(I)s = 318-873 nM. Isozyme hCA IX was inhibited with K(I)s = 11.8-93.4 nM, and hCA XII with 23.5-82.3 nM. Compounds 12-14, 27 and 29-31 have an activity against hCA I (K(I)s = 224-889 nM) which is comparable to the clinically used sulfonamide DCP (K(I)s = 1200 nM). Several of new compounds, including 9, 10, 21, 24, 26-28 and 30 have an activity against hCA IX (K(I)s = 11.8-38.6 nM) which is comparable or more effective than the clinically used sulfonamides AAZ, MZA, EZA, DCP and IND (K(I)s = 24-50 nM). Compounds 9, 10, 13, 21-23, 26 and 27 were also very effective hCA XII inhibitors, with inhibition constants ranged from 23.5 to 47.2 nM comparable or more effective than sulfonamides EZA (K(I)s = 22 nM) or DCP (K(I)s = 50 nM), respectively.

Authors+Show Affiliations

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

Pub Type(s)

Journal Article

Language

eng

PubMed ID

22910138

Citation

Brzozowski, Zdzisław, et al. "Carbonic Anhydrase Inhibitors. Regioselective Synthesis of Novel Series 1-substituted 1,4-dihydro-4-oxo-3-pyridinesulfonamides and Their Inhibition of the Human Cytosolic Isozymes I and II and Transmembrane Cancer-associated Isozymes IX and XII." European Journal of Medicinal Chemistry, vol. 56, 2012, pp. 282-91.
Brzozowski Z, Sławiński J, Vullo D, et al. Carbonic anhydrase inhibitors. Regioselective synthesis of novel series 1-substituted 1,4-dihydro-4-oxo-3-pyridinesulfonamides and their inhibition of the human cytosolic isozymes I and II and transmembrane cancer-associated isozymes IX and XII. Eur J Med Chem. 2012;56:282-91.
Brzozowski, Z., Sławiński, J., Vullo, D., & Supuran, C. T. (2012). Carbonic anhydrase inhibitors. Regioselective synthesis of novel series 1-substituted 1,4-dihydro-4-oxo-3-pyridinesulfonamides and their inhibition of the human cytosolic isozymes I and II and transmembrane cancer-associated isozymes IX and XII. European Journal of Medicinal Chemistry, 56, 282-91. https://doi.org/10.1016/j.ejmech.2012.08.006
Brzozowski Z, et al. Carbonic Anhydrase Inhibitors. Regioselective Synthesis of Novel Series 1-substituted 1,4-dihydro-4-oxo-3-pyridinesulfonamides and Their Inhibition of the Human Cytosolic Isozymes I and II and Transmembrane Cancer-associated Isozymes IX and XII. Eur J Med Chem. 2012;56:282-91. PubMed PMID: 22910138.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Carbonic anhydrase inhibitors. Regioselective synthesis of novel series 1-substituted 1,4-dihydro-4-oxo-3-pyridinesulfonamides and their inhibition of the human cytosolic isozymes I and II and transmembrane cancer-associated isozymes IX and XII. AU - Brzozowski,Zdzisław, AU - Sławiński,Jarosław, AU - Vullo,Daniela, AU - Supuran,Claudiu T, Y1 - 2012/08/11/ PY - 2012/03/21/received PY - 2012/07/17/revised PY - 2012/08/02/accepted PY - 2012/8/23/entrez PY - 2012/8/23/pubmed PY - 2013/5/10/medline SP - 282 EP - 91 JF - European journal of medicinal chemistry JO - Eur J Med Chem VL - 56 N2 - A series of novel 1-substituted 1,4-dihydro-4-oxo-3-pyridinesulfonamides 4-6, 9-17 and 21-31 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 cancer-associated isozymes CA IX and XII. Against the human isozymes hCA I the new compounds showed K(I)s in the range of 224-4830 nM, whereas toward hCA II, K(I)s = 318-873 nM. Isozyme hCA IX was inhibited with K(I)s = 11.8-93.4 nM, and hCA XII with 23.5-82.3 nM. Compounds 12-14, 27 and 29-31 have an activity against hCA I (K(I)s = 224-889 nM) which is comparable to the clinically used sulfonamide DCP (K(I)s = 1200 nM). Several of new compounds, including 9, 10, 21, 24, 26-28 and 30 have an activity against hCA IX (K(I)s = 11.8-38.6 nM) which is comparable or more effective than the clinically used sulfonamides AAZ, MZA, EZA, DCP and IND (K(I)s = 24-50 nM). Compounds 9, 10, 13, 21-23, 26 and 27 were also very effective hCA XII inhibitors, with inhibition constants ranged from 23.5 to 47.2 nM comparable or more effective than sulfonamides EZA (K(I)s = 22 nM) or DCP (K(I)s = 50 nM), respectively. SN - 1768-3254 UR - https://www.unboundmedicine.com/medline/citation/22910138/Carbonic_anhydrase_inhibitors__Regioselective_synthesis_of_novel_series_1_substituted_14_dihydro_4_oxo_3_pyridinesulfonamides_and_their_inhibition_of_the_human_cytosolic_isozymes_I_and_II_and_transmembrane_cancer_associated_isozymes_IX_and_XII_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0223-5234(12)00485-0 DB - PRIME DP - Unbound Medicine ER -