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Carbonic anhydrase inhibitors: inhibition of human cytosolic isozymes I and II and tumor-associated isozymes IX and XII with S-substituted 4-chloro-2-mercapto-5-methyl-benzenesulfonamides.
Bioorg Med Chem. 2008 Apr 01; 16(7):3933-40.BM

Abstract

A series of S-substituted 4-chloro-2-mercapto-5-methyl-benzenesulfonamides has been investigated as inhibitors of four isoforms of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), that is, the cytosolic, ubiquitous isozymes CA I and II, as well as the transmembrane, tumor-associated isozymes CA IX and XII. The new derivatives were inefficient inhibitors of isoform I (K(I)s in the range of 2.7-18.7 microM) but generally had low nanomolar affinity for the inhibition of the other three isoforms (K(I)s in the range of 2.4-214 nM against hCA II; 1.4-47.5 nM against hCA IX, and 1.7-569 nM against hCA XII, respectively). Some selectivity for the inhibition of the tumor-associated versus the cyctosolic isoform II with some of these compounds has also been evidenced. As CA IX is an important marker of tumor hypoxia and its predictive, prognostic, and druggability potentials for designing antitumor therapies were recently validated, detection of selective, potent CA IX inhibitors may be relevant in the fight against cancers overexpressing CA isozymes.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Saczewski F
Department of Chemical Technology of Drugs, Medical University of Gdansk, 80-416 Gdansk, Poland.
Innocenti A
No affiliation info available
Sławiński J
No affiliation info available
Kornicka A
No affiliation info available
Brzozowski Z
No affiliation info available
Pomarnacka E
No affiliation info available
Scozzafava A
No affiliation info available
Temperini C
No affiliation info available
Supuran CT
No affiliation info available

MeSH

Binding SitesCarbonic Anhydrase InhibitorsCarbonic AnhydrasesCytosolHumansHydrocarbons, ChlorinatedIsoenzymesMethylationModels, MolecularMolecular Sequence DataMolecular StructureNeoplasmsProtein FoldingSequence AlignmentStructure-Activity RelationshipSulfhydryl CompoundsSulfonamides

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18242998

Citation

Saczewski, Franciszek, et al. "Carbonic Anhydrase Inhibitors: Inhibition of Human Cytosolic Isozymes I and II and Tumor-associated Isozymes IX and XII With S-substituted 4-chloro-2-mercapto-5-methyl-benzenesulfonamides." Bioorganic & Medicinal Chemistry, vol. 16, no. 7, 2008, pp. 3933-40.
Saczewski F, Innocenti A, Sławiński J, et al. Carbonic anhydrase inhibitors: inhibition of human cytosolic isozymes I and II and tumor-associated isozymes IX and XII with S-substituted 4-chloro-2-mercapto-5-methyl-benzenesulfonamides. Bioorg Med Chem. 2008;16(7):3933-40.
Saczewski, F., Innocenti, A., Sławiński, J., Kornicka, A., Brzozowski, Z., Pomarnacka, E., Scozzafava, A., Temperini, C., & Supuran, C. T. (2008). Carbonic anhydrase inhibitors: inhibition of human cytosolic isozymes I and II and tumor-associated isozymes IX and XII with S-substituted 4-chloro-2-mercapto-5-methyl-benzenesulfonamides. Bioorganic & Medicinal Chemistry, 16(7), 3933-40. https://doi.org/10.1016/j.bmc.2008.01.034
Saczewski F, et al. Carbonic Anhydrase Inhibitors: Inhibition of Human Cytosolic Isozymes I and II and Tumor-associated Isozymes IX and XII With S-substituted 4-chloro-2-mercapto-5-methyl-benzenesulfonamides. Bioorg Med Chem. 2008 Apr 1;16(7):3933-40. PubMed PMID: 18242998.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Carbonic anhydrase inhibitors: inhibition of human cytosolic isozymes I and II and tumor-associated isozymes IX and XII with S-substituted 4-chloro-2-mercapto-5-methyl-benzenesulfonamides. AU - Saczewski,Franciszek, AU - Innocenti,Alessio, AU - Sławiński,Jarosław, AU - Kornicka,Anita, AU - Brzozowski,Zdzisław, AU - Pomarnacka,Elzbieta, AU - Scozzafava,Andrea, AU - Temperini,Claudia, AU - Supuran,Claudiu T, Y1 - 2008/01/26/ PY - 2007/09/30/received PY - 2008/01/14/revised PY - 2008/01/18/accepted PY - 2008/2/5/pubmed PY - 2008/5/16/medline PY - 2008/2/5/entrez SP - 3933 EP - 40 JF - Bioorganic & medicinal chemistry JO - Bioorg Med Chem VL - 16 IS - 7 N2 - A series of S-substituted 4-chloro-2-mercapto-5-methyl-benzenesulfonamides has been investigated as inhibitors of four isoforms of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), that is, the cytosolic, ubiquitous isozymes CA I and II, as well as the transmembrane, tumor-associated isozymes CA IX and XII. The new derivatives were inefficient inhibitors of isoform I (K(I)s in the range of 2.7-18.7 microM) but generally had low nanomolar affinity for the inhibition of the other three isoforms (K(I)s in the range of 2.4-214 nM against hCA II; 1.4-47.5 nM against hCA IX, and 1.7-569 nM against hCA XII, respectively). Some selectivity for the inhibition of the tumor-associated versus the cyctosolic isoform II with some of these compounds has also been evidenced. As CA IX is an important marker of tumor hypoxia and its predictive, prognostic, and druggability potentials for designing antitumor therapies were recently validated, detection of selective, potent CA IX inhibitors may be relevant in the fight against cancers overexpressing CA isozymes. SN - 1464-3391 UR - https://www.unboundmedicine.com/medline/citation/18242998 DB - PRIME DP - Unbound Medicine ER -
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