5-Aryl-1H-pyrazole-3-carboxylic acids as selective inhibitors of human carbonic anhydrases IX and XII
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2015
Authors
Cvijetić, IlijaTanç, Muhammet
Juranić, Ivan O.
Verbić, Tatjana
Supuran, Claudiu T.
Drakulić, Branko J.
Article (Published version)
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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.
Keywords:
Carbonic anhydrase / Phenyl-pyrazole-carboxylic acids / Docking / Molecular interaction fields / Active sites comparisonSource:
Bioorganic and Medicinal Chemistry, 2015, 23, 15, 4649-4659Publisher:
- Pergamon-Elsevier Science Ltd, Oxford
Funding / projects:
- Rational design and synthesis of biologically active and coordination compounds and functional materials, relevant for (bio)nanotechnology (RS-MESTD-Basic Research (BR or ON)-172035)
- EU
Note:
- Peer-reviewed manuscript: http://cherry.chem.bg.ac.rs/handle/123456789/3327
- Supplementary material: http://cherry.chem.bg.ac.rs/handle/123456789/3328
DOI: 10.1016/j.bmc.2015.05.052
ISSN: 0968-0896
PubMed: 26088336
WoS: 000358440000055
Scopus: 2-s2.0-84937818628
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Hemijski fakultet / Faculty of ChemistryTY - JOUR AU - Cvijetić, Ilija AU - Tanç, Muhammet AU - Juranić, Ivan O. AU - Verbić, Tatjana AU - Supuran, Claudiu T. AU - Drakulić, Branko J. PY - 2015 UR - https://cherry.chem.bg.ac.rs/handle/123456789/1742 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. PB - Pergamon-Elsevier Science Ltd, Oxford 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 Tanç, Muhammet and Juranić, Ivan O. and Verbić, Tatjana and Supuran, Claudiu T. and Drakulić, Branko J.", 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.", publisher = "Pergamon-Elsevier Science Ltd, Oxford", 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., Tanç, M., Juranić, I. O., Verbić, T., Supuran, C. T.,& Drakulić, B. J.. (2015). 5-Aryl-1H-pyrazole-3-carboxylic acids as selective inhibitors of human carbonic anhydrases IX and XII. in Bioorganic and Medicinal Chemistry Pergamon-Elsevier Science Ltd, Oxford., 23(15), 4649-4659. https://doi.org/10.1016/j.bmc.2015.05.052
Cvijetić I, Tanç M, Juranić IO, Verbić T, Supuran CT, Drakulić BJ. 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, Tanç, Muhammet, Juranić, Ivan O., Verbić, Tatjana, Supuran, Claudiu T., Drakulić, Branko J., "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 . .