Synthesis, computational studies and assessment of in vitro inhibitory activity of umbelliferon-based compounds against tumour-associated carbonic anhydrase isoforms IX and XII
Coumarins are widely diffused secondary metabolites possessing a plethora of biological activities. It has been established that coumarins represent a peculiar class of human carbonic anhydrase (hCA) inhibitors having a distinct mechanism of action involving a non-classical binding with amino acid r...
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doaj-b9a0619ad7554f53a19200f06463717b2021-07-15T13:10:33ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742020-01-013511442144910.1080/14756366.2020.17868211786821Synthesis, computational studies and assessment of in vitro inhibitory activity of umbelliferon-based compounds against tumour-associated carbonic anhydrase isoforms IX and XIIFrancesca Mancuso0Laura De Luca1Andrea Angeli2Sonia Del Prete3Clemente Capasso4Claudiu T. Supuran5Rosaria Gitto6Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche ed Ambientali (CHIBIOFARAM), Università degli Studi di MessinaDipartimento di Scienze Chimiche, Biologiche, Farmaceutiche ed Ambientali (CHIBIOFARAM), Università degli Studi di MessinaDipartimento NEUROFARBA, Università di FirenzeIstituto di Bioscienze e Biorisorse – CNRIstituto di Bioscienze e Biorisorse – CNRDipartimento NEUROFARBA, Università di FirenzeDipartimento di Scienze Chimiche, Biologiche, Farmaceutiche ed Ambientali (CHIBIOFARAM), Università degli Studi di MessinaCoumarins are widely diffused secondary metabolites possessing a plethora of biological activities. It has been established that coumarins represent a peculiar class of human carbonic anhydrase (hCA) inhibitors having a distinct mechanism of action involving a non-classical binding with amino acid residues paving the entrance of hCA catalytic site. Herein, we report the synthesis of a small series of new coumarin derivatives 7-11, 15, 17 prepared via classical Pechmann condensation starting from resorcinol derivatives and suitable β-ketoesters. The evaluation of inhibitory activity revealed that these compounds possessed nanomolar affinity and high selectivity towards tumour-associated hCA IX and XII over cytosolic hCA I and hCA II isoforms. To investigate the binding mode of these new coumarin-inspired inhibitors, the most active compounds 10 and 17 were docked within hCA XII catalytic cleft.http://dx.doi.org/10.1080/14756366.2020.1786821carbonic anhydrase inhibitors (cais)tumour-associated ca isoformscoumarinpechmann condensationfries rearrangement |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Francesca Mancuso Laura De Luca Andrea Angeli Sonia Del Prete Clemente Capasso Claudiu T. Supuran Rosaria Gitto |
spellingShingle |
Francesca Mancuso Laura De Luca Andrea Angeli Sonia Del Prete Clemente Capasso Claudiu T. Supuran Rosaria Gitto Synthesis, computational studies and assessment of in vitro inhibitory activity of umbelliferon-based compounds against tumour-associated carbonic anhydrase isoforms IX and XII Journal of Enzyme Inhibition and Medicinal Chemistry carbonic anhydrase inhibitors (cais) tumour-associated ca isoforms coumarin pechmann condensation fries rearrangement |
author_facet |
Francesca Mancuso Laura De Luca Andrea Angeli Sonia Del Prete Clemente Capasso Claudiu T. Supuran Rosaria Gitto |
author_sort |
Francesca Mancuso |
title |
Synthesis, computational studies and assessment of in vitro inhibitory activity of umbelliferon-based compounds against tumour-associated carbonic anhydrase isoforms IX and XII |
title_short |
Synthesis, computational studies and assessment of in vitro inhibitory activity of umbelliferon-based compounds against tumour-associated carbonic anhydrase isoforms IX and XII |
title_full |
Synthesis, computational studies and assessment of in vitro inhibitory activity of umbelliferon-based compounds against tumour-associated carbonic anhydrase isoforms IX and XII |
title_fullStr |
Synthesis, computational studies and assessment of in vitro inhibitory activity of umbelliferon-based compounds against tumour-associated carbonic anhydrase isoforms IX and XII |
title_full_unstemmed |
Synthesis, computational studies and assessment of in vitro inhibitory activity of umbelliferon-based compounds against tumour-associated carbonic anhydrase isoforms IX and XII |
title_sort |
synthesis, computational studies and assessment of in vitro inhibitory activity of umbelliferon-based compounds against tumour-associated carbonic anhydrase isoforms ix and xii |
publisher |
Taylor & Francis Group |
series |
Journal of Enzyme Inhibition and Medicinal Chemistry |
issn |
1475-6366 1475-6374 |
publishDate |
2020-01-01 |
description |
Coumarins are widely diffused secondary metabolites possessing a plethora of biological activities. It has been established that coumarins represent a peculiar class of human carbonic anhydrase (hCA) inhibitors having a distinct mechanism of action involving a non-classical binding with amino acid residues paving the entrance of hCA catalytic site. Herein, we report the synthesis of a small series of new coumarin derivatives 7-11, 15, 17 prepared via classical Pechmann condensation starting from resorcinol derivatives and suitable β-ketoesters. The evaluation of inhibitory activity revealed that these compounds possessed nanomolar affinity and high selectivity towards tumour-associated hCA IX and XII over cytosolic hCA I and hCA II isoforms. To investigate the binding mode of these new coumarin-inspired inhibitors, the most active compounds 10 and 17 were docked within hCA XII catalytic cleft. |
topic |
carbonic anhydrase inhibitors (cais) tumour-associated ca isoforms coumarin pechmann condensation fries rearrangement |
url |
http://dx.doi.org/10.1080/14756366.2020.1786821 |
work_keys_str_mv |
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1721300962871607296 |