2-Aminobenzoxazole-appended coumarins as potent and selective inhibitors of tumour-associated carbonic anhydrases
We have carried out the design, synthesis, and evaluation of a small library of 2-aminobenzoxazole-appended coumarins as novel inhibitors of tumour-related CAs IX and XII. Substituents on C-3 and/or C-4 positions of the coumarin scaffold, and on the benzoxazole moiety, together with the length of th...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2022-01-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/14756366.2021.1998026 |
| _version_ | 1819177275776565248 |
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| author | Alma Fuentes-Aguilar Penélope Merino-Montiel Sara Montiel-Smith Socorro Meza-Reyes José Luis Vega-Báez Adrián Puerta Miguel X. Fernandes José M. Padrón Andrea Petreni Alessio Nocentini Claudiu T. Supuran Óscar López José G. Fernández-Bolaños |
| author_facet | Alma Fuentes-Aguilar Penélope Merino-Montiel Sara Montiel-Smith Socorro Meza-Reyes José Luis Vega-Báez Adrián Puerta Miguel X. Fernandes José M. Padrón Andrea Petreni Alessio Nocentini Claudiu T. Supuran Óscar López José G. Fernández-Bolaños |
| author_sort | Alma Fuentes-Aguilar |
| collection | DOAJ |
| description | We have carried out the design, synthesis, and evaluation of a small library of 2-aminobenzoxazole-appended coumarins as novel inhibitors of tumour-related CAs IX and XII. Substituents on C-3 and/or C-4 positions of the coumarin scaffold, and on the benzoxazole moiety, together with the length of the linker connecting both units were modified to obtain useful structure-activity relationships. CA inhibition studies revealed a good selectivity towards tumour-associated CAs IX and XII (Ki within the mid-nanomolar range in most of the cases) in comparison with CAs I, II, IV, and VII (Ki > 10 µM); CA IX was found to be slightly more sensitive towards structural changes. Docking calculations suggested that the coumarin scaffold might act as a prodrug, binding to the CAs in its hydrolysed form, which is in turn obtained due to the esterase activity of CAs. An increase of the tether length and of the substituents steric hindrance was found to be detrimental to in vitro antiproliferative activities. Incorporation of a chlorine atom on C-3 of the coumarin moiety achieved the strongest antiproliferative agent, with activities within the low micromolar range for the panel of tumour cell lines tested. |
| first_indexed | 2024-12-22T21:24:04Z |
| format | Article |
| id | doaj.art-a6eef15339bd494b8cace42877923ed9 |
| institution | Directory Open Access Journal |
| issn | 1475-6366 1475-6374 |
| language | English |
| last_indexed | 2024-12-22T21:24:04Z |
| publishDate | 2022-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj.art-a6eef15339bd494b8cace42877923ed92022-12-21T18:12:07ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742022-01-0137116817710.1080/14756366.2021.199802619980262-Aminobenzoxazole-appended coumarins as potent and selective inhibitors of tumour-associated carbonic anhydrasesAlma Fuentes-Aguilar0Penélope Merino-Montiel1Sara Montiel-Smith2Socorro Meza-Reyes3José Luis Vega-Báez4Adrián Puerta5Miguel X. Fernandes6José M. Padrón7Andrea Petreni8Alessio Nocentini9Claudiu T. Supuran10Óscar López11José G. Fernández-Bolaños12Facultad de Ciencias Químicas, Ciudad Universitaria, Benemérita Universidad Autónoma de PueblaFacultad de Ciencias Químicas, Ciudad Universitaria, Benemérita Universidad Autónoma de PueblaFacultad de Ciencias Químicas, Ciudad Universitaria, Benemérita Universidad Autónoma de PueblaFacultad de Ciencias Químicas, Ciudad Universitaria, Benemérita Universidad Autónoma de PueblaFacultad de Ciencias Químicas, Ciudad Universitaria, Benemérita Universidad Autónoma de PueblaBioLab, Instituto Universitario de Bio-Orgánica “Antonio González” (IUBO-AG), Universidad de La LagunaBioLab, Instituto Universitario de Bio-Orgánica “Antonio González” (IUBO-AG), Universidad de La LagunaBioLab, Instituto Universitario de Bio-Orgánica “Antonio González” (IUBO-AG), Universidad de La LagunaNEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, University of FlorenceNEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, University of FlorenceNEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, University of FlorenceDepartamento de Química Orgánica, Facultad de Química, Universidad de SevillaDepartamento de Química Orgánica, Facultad de Química, Universidad de SevillaWe have carried out the design, synthesis, and evaluation of a small library of 2-aminobenzoxazole-appended coumarins as novel inhibitors of tumour-related CAs IX and XII. Substituents on C-3 and/or C-4 positions of the coumarin scaffold, and on the benzoxazole moiety, together with the length of the linker connecting both units were modified to obtain useful structure-activity relationships. CA inhibition studies revealed a good selectivity towards tumour-associated CAs IX and XII (Ki within the mid-nanomolar range in most of the cases) in comparison with CAs I, II, IV, and VII (Ki > 10 µM); CA IX was found to be slightly more sensitive towards structural changes. Docking calculations suggested that the coumarin scaffold might act as a prodrug, binding to the CAs in its hydrolysed form, which is in turn obtained due to the esterase activity of CAs. An increase of the tether length and of the substituents steric hindrance was found to be detrimental to in vitro antiproliferative activities. Incorporation of a chlorine atom on C-3 of the coumarin moiety achieved the strongest antiproliferative agent, with activities within the low micromolar range for the panel of tumour cell lines tested.http://dx.doi.org/10.1080/14756366.2021.1998026carbonic anhydrasescoumarinsbenzoxazolesantiproliferative agentsdocking |
| spellingShingle | Alma Fuentes-Aguilar Penélope Merino-Montiel Sara Montiel-Smith Socorro Meza-Reyes José Luis Vega-Báez Adrián Puerta Miguel X. Fernandes José M. Padrón Andrea Petreni Alessio Nocentini Claudiu T. Supuran Óscar López José G. Fernández-Bolaños 2-Aminobenzoxazole-appended coumarins as potent and selective inhibitors of tumour-associated carbonic anhydrases Journal of Enzyme Inhibition and Medicinal Chemistry carbonic anhydrases coumarins benzoxazoles antiproliferative agents docking |
| title | 2-Aminobenzoxazole-appended coumarins as potent and selective inhibitors of tumour-associated carbonic anhydrases |
| title_full | 2-Aminobenzoxazole-appended coumarins as potent and selective inhibitors of tumour-associated carbonic anhydrases |
| title_fullStr | 2-Aminobenzoxazole-appended coumarins as potent and selective inhibitors of tumour-associated carbonic anhydrases |
| title_full_unstemmed | 2-Aminobenzoxazole-appended coumarins as potent and selective inhibitors of tumour-associated carbonic anhydrases |
| title_short | 2-Aminobenzoxazole-appended coumarins as potent and selective inhibitors of tumour-associated carbonic anhydrases |
| title_sort | 2 aminobenzoxazole appended coumarins as potent and selective inhibitors of tumour associated carbonic anhydrases |
| topic | carbonic anhydrases coumarins benzoxazoles antiproliferative agents docking |
| url | http://dx.doi.org/10.1080/14756366.2021.1998026 |
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