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Synthesis of potent and selective HDAC6 inhibitors led to unexpected opening of a quinazoline ring
Histone deacetylase (HDAC) inhibitors are highly involved in the regulation of many pharmacological responses, which results in anti-inflammatory and anti-cancer effects. In the present work, chemoinformatic analyses were performed to obtain two potent and selective aminotriazoloquinazoline-based HD...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Royal Society of Chemistry
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9006239/ https://www.ncbi.nlm.nih.gov/pubmed/35425078 http://dx.doi.org/10.1039/d2ra01753a |
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author | Moi, Davide Citarella, Andrea Bonanni, Davide Pinzi, Luca Passarella, Daniele Silvani, Alessandra Giannini, Clelia Rastelli, Giulio |
author_facet | Moi, Davide Citarella, Andrea Bonanni, Davide Pinzi, Luca Passarella, Daniele Silvani, Alessandra Giannini, Clelia Rastelli, Giulio |
author_sort | Moi, Davide |
collection | PubMed |
description | Histone deacetylase (HDAC) inhibitors are highly involved in the regulation of many pharmacological responses, which results in anti-inflammatory and anti-cancer effects. In the present work, chemoinformatic analyses were performed to obtain two potent and selective aminotriazoloquinazoline-based HDAC6 inhibitors. We unexpectedly obtained an aminotriazole from a water-driven ring opening of the triazoloquinazoline scaffold. Both compounds were evaluated as HDAC6 inhibitors, resulting in subnanomolar inhibitory activity and high selectivity with respect to class I HDAC1 and HDAC8. Importantly, the compounds were about 3- and 15-fold more potent compared to the reference compound trichostatin A. Additionally, the predicted binding modes were investigated with docking. Considering that the aminotriazole scaffold has never been embedded into the chemical structure of HDAC6 inhibitors, the present study suggests that both the aminotriazoloquinazoline and aminotriazole classes of compounds could be excellent starting points for further optimization of potential anticancer compounds, introducing such novel groups into a relevant and new area of investigation. |
format | Online Article Text |
id | pubmed-9006239 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | The Royal Society of Chemistry |
record_format | MEDLINE/PubMed |
spelling | pubmed-90062392022-04-13 Synthesis of potent and selective HDAC6 inhibitors led to unexpected opening of a quinazoline ring Moi, Davide Citarella, Andrea Bonanni, Davide Pinzi, Luca Passarella, Daniele Silvani, Alessandra Giannini, Clelia Rastelli, Giulio RSC Adv Chemistry Histone deacetylase (HDAC) inhibitors are highly involved in the regulation of many pharmacological responses, which results in anti-inflammatory and anti-cancer effects. In the present work, chemoinformatic analyses were performed to obtain two potent and selective aminotriazoloquinazoline-based HDAC6 inhibitors. We unexpectedly obtained an aminotriazole from a water-driven ring opening of the triazoloquinazoline scaffold. Both compounds were evaluated as HDAC6 inhibitors, resulting in subnanomolar inhibitory activity and high selectivity with respect to class I HDAC1 and HDAC8. Importantly, the compounds were about 3- and 15-fold more potent compared to the reference compound trichostatin A. Additionally, the predicted binding modes were investigated with docking. Considering that the aminotriazole scaffold has never been embedded into the chemical structure of HDAC6 inhibitors, the present study suggests that both the aminotriazoloquinazoline and aminotriazole classes of compounds could be excellent starting points for further optimization of potential anticancer compounds, introducing such novel groups into a relevant and new area of investigation. The Royal Society of Chemistry 2022-04-13 /pmc/articles/PMC9006239/ /pubmed/35425078 http://dx.doi.org/10.1039/d2ra01753a Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by/3.0/ |
spellingShingle | Chemistry Moi, Davide Citarella, Andrea Bonanni, Davide Pinzi, Luca Passarella, Daniele Silvani, Alessandra Giannini, Clelia Rastelli, Giulio Synthesis of potent and selective HDAC6 inhibitors led to unexpected opening of a quinazoline ring |
title | Synthesis of potent and selective HDAC6 inhibitors led to unexpected opening of a quinazoline ring |
title_full | Synthesis of potent and selective HDAC6 inhibitors led to unexpected opening of a quinazoline ring |
title_fullStr | Synthesis of potent and selective HDAC6 inhibitors led to unexpected opening of a quinazoline ring |
title_full_unstemmed | Synthesis of potent and selective HDAC6 inhibitors led to unexpected opening of a quinazoline ring |
title_short | Synthesis of potent and selective HDAC6 inhibitors led to unexpected opening of a quinazoline ring |
title_sort | synthesis of potent and selective hdac6 inhibitors led to unexpected opening of a quinazoline ring |
topic | Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9006239/ https://www.ncbi.nlm.nih.gov/pubmed/35425078 http://dx.doi.org/10.1039/d2ra01753a |
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