5-Aryl-1H-pyrazole-3-carboxylic acids as selective inhibitors of human carbonic anhydrases IX and XII
Authors
Cvijetić, Ilija
Tanc, Muhammet
Juranić, Ivan

Verbić, Tatjana

Supuran, Claudiu T.
Drakulić, Branko

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Inhibitory activity of a congeneric set of 23 phenyl-substituted 5-phenyl-pyrazole-3-carboxylic acids toward human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms I, II, IX and XII was evaluated by a stopped-flow CO2 hydrase assay. These compounds exerted a clear, selective inhibition of hCA IX and XII over hCAI and II, with Ki in two to one digit micromolar concentrations (4-50 mu M). Derivatives bearing bulkier substituents in para-position of the phenyl ring inhibited hCA XII at one-digit micromolar concentrations, while derivatives having alkyl substituents in both ortho-and meta-positions inhibited hCA IX with Kis ranging between 5 and 25 mu M. Results of docking experiments offered a rational explanation on the selectivity of these compounds toward CA IX and XII, as well as on the substitution patterns leading to best CA IX or CA XII inhibitors. By examining the active sites of these four isoforms with GRID generated molecular-interaction fields, striking differences between hCA XI...I and the other three isoforms were observed. The field of hydrophobic probe (DRY) appeared significantly different in CA XII active site, comparing to other three isoforms studied. To the best of our knowledge such an observation was not reported in literature so far. Considering the selectivity of these carboxylates towards membrane-associated over cytosolic CA isoforms, the title compounds could be useful for the development of isoform-specific non-sulfonamide CA inhibitors. (C) 2015 Elsevier Ltd. All rights reserved.
Keywords:
Carbonic anhydrase / Phenyl-pyrazole-carboxylic acids / Docking / Molecular interaction fields / Active sites comparisonSource:
Bioorganic and Medicinal Chemistry, 2015, 23, 15, 4649-4659Publisher:
- Oxford : Pergamon-Elsevier Science Ltd
Funding / projects:
Note:
- This is the peer-reviewed version of the article: https://doi.org/10.1016/j.bmc.2015.05.052
- The published version of the article: http://cer.ihtm.bg.ac.rs/handle/123456789/2872
DOI: 10.1016/j.bmc.2015.05.052
ISSN: 0968-0896
PubMed: 26088336
WoS: 000358440000055
Scopus: 2-s2.0-84937818628
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IHTMTY - JOUR AU - Cvijetić, Ilija AU - Tanc, Muhammet AU - Juranić, Ivan AU - Verbić, Tatjana AU - Supuran, Claudiu T. AU - Drakulić, Branko PY - 2015 UR - https://cer.ihtm.bg.ac.rs/handle/123456789/2668 AB - Inhibitory activity of a congeneric set of 23 phenyl-substituted 5-phenyl-pyrazole-3-carboxylic acids toward human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms I, II, IX and XII was evaluated by a stopped-flow CO2 hydrase assay. These compounds exerted a clear, selective inhibition of hCA IX and XII over hCAI and II, with Ki in two to one digit micromolar concentrations (4-50 mu M). Derivatives bearing bulkier substituents in para-position of the phenyl ring inhibited hCA XII at one-digit micromolar concentrations, while derivatives having alkyl substituents in both ortho-and meta-positions inhibited hCA IX with Kis ranging between 5 and 25 mu M. Results of docking experiments offered a rational explanation on the selectivity of these compounds toward CA IX and XII, as well as on the substitution patterns leading to best CA IX or CA XII inhibitors. By examining the active sites of these four isoforms with GRID generated molecular-interaction fields, striking differences between hCA XII and the other three isoforms were observed. The field of hydrophobic probe (DRY) appeared significantly different in CA XII active site, comparing to other three isoforms studied. To the best of our knowledge such an observation was not reported in literature so far. Considering the selectivity of these carboxylates towards membrane-associated over cytosolic CA isoforms, the title compounds could be useful for the development of isoform-specific non-sulfonamide CA inhibitors. (C) 2015 Elsevier Ltd. All rights reserved. PB - Oxford : Pergamon-Elsevier Science Ltd T2 - Bioorganic and Medicinal Chemistry T1 - 5-Aryl-1H-pyrazole-3-carboxylic acids as selective inhibitors of human carbonic anhydrases IX and XII VL - 23 IS - 15 SP - 4649 EP - 4659 DO - 10.1016/j.bmc.2015.05.052 ER -
@article{ author = "Cvijetić, Ilija and Tanc, Muhammet and Juranić, Ivan and Verbić, Tatjana and Supuran, Claudiu T. and Drakulić, Branko", year = "2015", abstract = "Inhibitory activity of a congeneric set of 23 phenyl-substituted 5-phenyl-pyrazole-3-carboxylic acids toward human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms I, II, IX and XII was evaluated by a stopped-flow CO2 hydrase assay. These compounds exerted a clear, selective inhibition of hCA IX and XII over hCAI and II, with Ki in two to one digit micromolar concentrations (4-50 mu M). Derivatives bearing bulkier substituents in para-position of the phenyl ring inhibited hCA XII at one-digit micromolar concentrations, while derivatives having alkyl substituents in both ortho-and meta-positions inhibited hCA IX with Kis ranging between 5 and 25 mu M. Results of docking experiments offered a rational explanation on the selectivity of these compounds toward CA IX and XII, as well as on the substitution patterns leading to best CA IX or CA XII inhibitors. By examining the active sites of these four isoforms with GRID generated molecular-interaction fields, striking differences between hCA XII and the other three isoforms were observed. The field of hydrophobic probe (DRY) appeared significantly different in CA XII active site, comparing to other three isoforms studied. To the best of our knowledge such an observation was not reported in literature so far. Considering the selectivity of these carboxylates towards membrane-associated over cytosolic CA isoforms, the title compounds could be useful for the development of isoform-specific non-sulfonamide CA inhibitors. (C) 2015 Elsevier Ltd. All rights reserved.", publisher = "Oxford : Pergamon-Elsevier Science Ltd", journal = "Bioorganic and Medicinal Chemistry", title = "5-Aryl-1H-pyrazole-3-carboxylic acids as selective inhibitors of human carbonic anhydrases IX and XII", volume = "23", number = "15", pages = "4649-4659", doi = "10.1016/j.bmc.2015.05.052" }
Cvijetić, I., Tanc, M., Juranić, I., Verbić, T., Supuran, C. T.,& Drakulić, B.. (2015). 5-Aryl-1H-pyrazole-3-carboxylic acids as selective inhibitors of human carbonic anhydrases IX and XII. in Bioorganic and Medicinal Chemistry Oxford : Pergamon-Elsevier Science Ltd., 23(15), 4649-4659. https://doi.org/10.1016/j.bmc.2015.05.052
Cvijetić I, Tanc M, Juranić I, Verbić T, Supuran CT, Drakulić B. 5-Aryl-1H-pyrazole-3-carboxylic acids as selective inhibitors of human carbonic anhydrases IX and XII. in Bioorganic and Medicinal Chemistry. 2015;23(15):4649-4659. doi:10.1016/j.bmc.2015.05.052 .
Cvijetić, Ilija, Tanc, Muhammet, Juranić, Ivan, Verbić, Tatjana, Supuran, Claudiu T., Drakulić, Branko, "5-Aryl-1H-pyrazole-3-carboxylic acids as selective inhibitors of human carbonic anhydrases IX and XII" in Bioorganic and Medicinal Chemistry, 23, no. 15 (2015):4649-4659, https://doi.org/10.1016/j.bmc.2015.05.052 . .