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Molecules 2018, 23(1), 153; https://doi.org/10.3390/molecules23010153

Novel 6- and 7-Substituted Coumarins with Inhibitory Action against Lipoxygenase and Tumor-Associated Carbonic Anhydrase IX

1
Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche e Nutraceutiche, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Firenze), Italy
2
Department of Pharmaceutical Chemistry, School of Pharmacy, Faculty of Health Sciences, 54124 Thessaloniki, Greece
3
Dipartimento di Chimica, Laboratorio di Chimica Bioinorganica, Università degli Studi di Firenze, Via della Lastruccia 3, 50019 Sesto Fiorentino (Firenze), Italy
*
Author to whom correspondence should be addressed.
Received: 11 December 2017 / Revised: 5 January 2018 / Accepted: 11 January 2018 / Published: 12 January 2018
(This article belongs to the Special Issue Metalloenzyme Inhibitors and Activators)
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Abstract

A series of carboxamide derivatives of 6- and 7-substituted coumarins have been prepared by an original procedure starting from the corresponding 6- or 7-hydroxycoumarins which were alkylated with ethyl iodoacetate, and the obtained ester was converted to the corresponding carboxylic acids which were thereafter reacted with a series of aromatic/aliphatic/heterocyclic amines leading to the desired amides. The new derivatives were investigated as inhibitors of two enzymes, human carbonic anhydrases (hCAs) and soy bean lipoxygenase (LOX). Compounds 4a and 4b were potent LOX inhibitors, whereas many effective hCA IX inhibitors (KIs in the range of 30.2–30.5 nM) were detected in this study. Two compounds, 4b and 5b, showed the phenomenon of dual inhibition. Furthermore, these coumarins did not significantly inhibit the widespread cytosolic isoforms hCA I and II, whereas they were weak hCA IV inhibitors, making them hCA IX-selective inhibitors. As hCA IX and LOX are validated antitumor targets, these results are promising for the investigation of novel drug targets involved in tumorigenesis. View Full-Text
Keywords: coumarins; carboxamides; carbonic anhydrase; lipoxygenase; enzyme inhibitor coumarins; carboxamides; carbonic anhydrase; lipoxygenase; enzyme inhibitor
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
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Peperidou, A.; Bua, S.; Bozdag, M.; Hadjipavlou-Litina, D.; Supuran, C.T. Novel 6- and 7-Substituted Coumarins with Inhibitory Action against Lipoxygenase and Tumor-Associated Carbonic Anhydrase IX. Molecules 2018, 23, 153.

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