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5-Aryl-1H-pyrazole-3-carboxylic acids as selective inhibitors of human carbonic anhydrases IX and XII

Authorized Users Only
2015
Authors
Cvijetić, Ilija
Tanç, Muhammet
Juranić, Ivan O.
Verbić, Tatjana
Supuran, Claudiu T.
Drakulić, Branko J.
Article (Published version)
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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 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 comparison
Source:
Bioorganic and Medicinal Chemistry, 2015, 23, 15, 4649-4659
Publisher:
  • 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-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
[ Google Scholar ]
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URI
https://cherry.chem.bg.ac.rs/handle/123456789/1742
Collections
  • Publikacije
  • Publikacije
Institution/Community
Hemijski fakultet
TY  - 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
UR  - Kon_2888
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",
url = "Kon_2888"
}
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
Kon_2888
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
Kon_2888 .
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 .,
Kon_2888 .

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