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Carbonic anhydrase inhibitors. Inhibition of the human cytosolic isoforms I and II and transmembrane, tumor-associated isoforms IX and XII with boronic acids.
Bioorg Med Chem. 2009 May 15; 17(10):3649-52.BM

Abstract

A series of aromatic, arylalkenyl- and arylalkyl boronic acids were assayed as inhibitors of four physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isoforms, the cytosolic human (h) hCA I and II, and the transmembrane, tumor-associated hCA IX and XII. The best hCA I and II inhibitor was biphenyl boronic acid with, a K(I) of 3.7-4.5 microM, whereas the remaining derivatives showed inhibition constants in the range of 6.0-1560 microM for hCA I and of 6.0-1050 microM for hCA II, respectively. hCA IX and XII were effectively inhibited by most of the aromatic boronic acids (K(I)s of 7.6-12.3 microM) whereas the arylalkenyl and aryl-alkyl derivatives generally showed weaker inhibitory properties (K(I)s of 34-531 microM). The nature of the moiety substituting the boronic acid group strongly influenced the CA inhibitory activity, with inhibitors possessing low micromolar to millimolar activity being detected in this small series of investigated compounds. This study proves that the B(OH)(2) moiety represents a new zinc-binding group for the generation of effective CA inhibitors targeting isoforms with medicinal chemistry applications. The boronic acids probably bind to the Zn(II) ion within the CA active site leading to a tetrahedral geometry of the metal ion and of the B(III) derivative.

Authors+Show Affiliations

Institut des Biomolécules Max Mousseron (IBMM) UMR 5247 CNRS-UM1-UM2 Bâtiment de Recherche Max Mousseron, Ecole Nationale Supérieure de Chimie de Montpellier, 8 rue de l'Ecole Normale, 34296 Montpellier Cedex, France.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

19375921

Citation

Winum, Jean-Yves, et al. "Carbonic Anhydrase Inhibitors. Inhibition of the Human Cytosolic Isoforms I and II and Transmembrane, Tumor-associated Isoforms IX and XII With Boronic Acids." Bioorganic & Medicinal Chemistry, vol. 17, no. 10, 2009, pp. 3649-52.
Winum JY, Innocenti A, Scozzafava A, et al. Carbonic anhydrase inhibitors. Inhibition of the human cytosolic isoforms I and II and transmembrane, tumor-associated isoforms IX and XII with boronic acids. Bioorg Med Chem. 2009;17(10):3649-52.
Winum, J. Y., Innocenti, A., Scozzafava, A., Montero, J. L., & Supuran, C. T. (2009). Carbonic anhydrase inhibitors. Inhibition of the human cytosolic isoforms I and II and transmembrane, tumor-associated isoforms IX and XII with boronic acids. Bioorganic & Medicinal Chemistry, 17(10), 3649-52. https://doi.org/10.1016/j.bmc.2009.03.058
Winum JY, et al. Carbonic Anhydrase Inhibitors. Inhibition of the Human Cytosolic Isoforms I and II and Transmembrane, Tumor-associated Isoforms IX and XII With Boronic Acids. Bioorg Med Chem. 2009 May 15;17(10):3649-52. PubMed PMID: 19375921.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Carbonic anhydrase inhibitors. Inhibition of the human cytosolic isoforms I and II and transmembrane, tumor-associated isoforms IX and XII with boronic acids. AU - Winum,Jean-Yves, AU - Innocenti,Alessio, AU - Scozzafava,Andrea, AU - Montero,Jean-Louis, AU - Supuran,Claudiu T, Y1 - 2009/04/05/ PY - 2009/03/02/received PY - 2009/03/22/revised PY - 2009/03/29/accepted PY - 2009/4/21/entrez PY - 2009/4/21/pubmed PY - 2009/7/1/medline SP - 3649 EP - 52 JF - Bioorganic & medicinal chemistry JO - Bioorg Med Chem VL - 17 IS - 10 N2 - A series of aromatic, arylalkenyl- and arylalkyl boronic acids were assayed as inhibitors of four physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isoforms, the cytosolic human (h) hCA I and II, and the transmembrane, tumor-associated hCA IX and XII. The best hCA I and II inhibitor was biphenyl boronic acid with, a K(I) of 3.7-4.5 microM, whereas the remaining derivatives showed inhibition constants in the range of 6.0-1560 microM for hCA I and of 6.0-1050 microM for hCA II, respectively. hCA IX and XII were effectively inhibited by most of the aromatic boronic acids (K(I)s of 7.6-12.3 microM) whereas the arylalkenyl and aryl-alkyl derivatives generally showed weaker inhibitory properties (K(I)s of 34-531 microM). The nature of the moiety substituting the boronic acid group strongly influenced the CA inhibitory activity, with inhibitors possessing low micromolar to millimolar activity being detected in this small series of investigated compounds. This study proves that the B(OH)(2) moiety represents a new zinc-binding group for the generation of effective CA inhibitors targeting isoforms with medicinal chemistry applications. The boronic acids probably bind to the Zn(II) ion within the CA active site leading to a tetrahedral geometry of the metal ion and of the B(III) derivative. SN - 1464-3391 UR - https://www.unboundmedicine.com/medline/citation/19375921/Carbonic_anhydrase_inhibitors__Inhibition_of_the_human_cytosolic_isoforms_I_and_II_and_transmembrane_tumor_associated_isoforms_IX_and_XII_with_boronic_acids_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0968-0896(09)00316-2 DB - PRIME DP - Unbound Medicine ER -