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

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2015
10.1016@j.bmc.2015.05.052_accepted.pdf (5.568Mb)
Authors
Cvijetić, Ilija
Tanc, Muhammet
Juranić, Ivan
Verbić, Tatjana
Supuran, Claudiu T.
Drakulić, Branko
Article (Accepted 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. (C) 2015 Elsevier Ltd. All rights reserved.

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:
  • Oxford : Pergamon-Elsevier Science Ltd
Funding / projects:
  • Rational design and synthesis of biologically active and coordination compounds and functional materials, relevant for (bio)nanotechnology (RS-172035)
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
[ Google Scholar ]
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URI
https://cer.ihtm.bg.ac.rs/handle/123456789/2668
Collections
  • Radovi istraživača / Researchers' publications
Institution/Community
IHTM
TY  - 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 . .

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