Design of Fluorescent Coumarin-Hydroxamic Acid Derivatives as Inhibitors of HDACs: Synthesis, Anti-Proliferative Evaluation and Docking Studies
Coumarin-hydroxamic acid derivatives <b>7a</b>–<b>k</b> were herein designed with a dual purpose: as antiproliferative agents and fluorescent probes. The compounds were synthesized in moderate yields (30–87%) through a simple methodology, biological evaluation was carried out...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-11-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/25/21/5134 |
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| author | Santiago García Itzel Mercado-Sánchez Luis Bahena Yolanda Alcaraz Marco A. García-Revilla Juvencio Robles Nancy Santos-Martínez David Ordaz-Rosado Rocío García-Becerra Miguel A. Vazquez |
| author_facet | Santiago García Itzel Mercado-Sánchez Luis Bahena Yolanda Alcaraz Marco A. García-Revilla Juvencio Robles Nancy Santos-Martínez David Ordaz-Rosado Rocío García-Becerra Miguel A. Vazquez |
| author_sort | Santiago García |
| collection | DOAJ |
| description | Coumarin-hydroxamic acid derivatives <b>7a</b>–<b>k</b> were herein designed with a dual purpose: as antiproliferative agents and fluorescent probes. The compounds were synthesized in moderate yields (30–87%) through a simple methodology, biological evaluation was carried out on prostate (PC3) and breast cancer (BT-474 and MDA-MB-231) cell lines to determine the effects on cell proliferation and gene expression. For compounds <b>7c</b>, <b>7e</b>, <b>7f</b>, <b>7i</b> and <b>7j</b> the inhibition of cancer cell proliferation was similar to that found with the reference compound at a comparable concentration (10 μM), in addition, their molecular docking studies performed on histone deacetylases 1, 6 and 8 showed strong binding to the respective active sites. In most cases, antiproliferative activity was accompanied by greater levels of cyclin-dependent kinase inhibitor p21, downregulation of the p53 tumor suppressor gene, and regulation of cyclin D1 gene expression. We conclude that compounds <b>7c</b>, <b>7e</b>, <b>7f</b>, <b>7i</b> and <b>7j</b> may be considered as potential anticancer agents, considering their antiproliferative properties, their effect on the regulation of the genes, as well as their capacity to dock to the active sites. The fluorescent properties of compound <b>7j</b> and <b>7k</b> suggest that they can provide further insight into the mechanism of action. |
| first_indexed | 2024-03-10T15:05:06Z |
| format | Article |
| id | doaj.art-712fae62cb1b4c7abf8c9b581b80c8ba |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T15:05:06Z |
| publishDate | 2020-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-712fae62cb1b4c7abf8c9b581b80c8ba2023-11-20T19:48:17ZengMDPI AGMolecules1420-30492020-11-012521513410.3390/molecules25215134Design of Fluorescent Coumarin-Hydroxamic Acid Derivatives as Inhibitors of HDACs: Synthesis, Anti-Proliferative Evaluation and Docking StudiesSantiago García0Itzel Mercado-Sánchez1Luis Bahena2Yolanda Alcaraz3Marco A. García-Revilla4Juvencio Robles5Nancy Santos-Martínez6David Ordaz-Rosado7Rocío García-Becerra8Miguel A. Vazquez9Departamento de Química, Universidad de Guanajuato, Guanajuato, Gto. 36050, MexicoDepartamento de Química, Universidad de Guanajuato, Guanajuato, Gto. 36050, MexicoDepartamento de Química, Universidad de Guanajuato, Guanajuato, Gto. 36050, MexicoDepartamento de Farmacia, Universidad de Guanajuato, Guanajuato, Gto. 36050, MexicoDepartamento de Química, Universidad de Guanajuato, Guanajuato, Gto. 36050, MexicoDepartamento de Farmacia, Universidad de Guanajuato, Guanajuato, Gto. 36050, MexicoDepartamento de Biología de la Reproducción Dr. Carlos Gual Castro, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México 14080, MexicoDepartamento de Biología de la Reproducción Dr. Carlos Gual Castro, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México 14080, MexicoDepartamento de Biología Molecular y Biotecnología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México 04510, MexicoDepartamento de Química, Universidad de Guanajuato, Guanajuato, Gto. 36050, MexicoCoumarin-hydroxamic acid derivatives <b>7a</b>–<b>k</b> were herein designed with a dual purpose: as antiproliferative agents and fluorescent probes. The compounds were synthesized in moderate yields (30–87%) through a simple methodology, biological evaluation was carried out on prostate (PC3) and breast cancer (BT-474 and MDA-MB-231) cell lines to determine the effects on cell proliferation and gene expression. For compounds <b>7c</b>, <b>7e</b>, <b>7f</b>, <b>7i</b> and <b>7j</b> the inhibition of cancer cell proliferation was similar to that found with the reference compound at a comparable concentration (10 μM), in addition, their molecular docking studies performed on histone deacetylases 1, 6 and 8 showed strong binding to the respective active sites. In most cases, antiproliferative activity was accompanied by greater levels of cyclin-dependent kinase inhibitor p21, downregulation of the p53 tumor suppressor gene, and regulation of cyclin D1 gene expression. We conclude that compounds <b>7c</b>, <b>7e</b>, <b>7f</b>, <b>7i</b> and <b>7j</b> may be considered as potential anticancer agents, considering their antiproliferative properties, their effect on the regulation of the genes, as well as their capacity to dock to the active sites. The fluorescent properties of compound <b>7j</b> and <b>7k</b> suggest that they can provide further insight into the mechanism of action.https://www.mdpi.com/1420-3049/25/21/5134coumarinshydroxamic acidsHDACgene expressionfluorescent probedocking analysis |
| spellingShingle | Santiago García Itzel Mercado-Sánchez Luis Bahena Yolanda Alcaraz Marco A. García-Revilla Juvencio Robles Nancy Santos-Martínez David Ordaz-Rosado Rocío García-Becerra Miguel A. Vazquez Design of Fluorescent Coumarin-Hydroxamic Acid Derivatives as Inhibitors of HDACs: Synthesis, Anti-Proliferative Evaluation and Docking Studies Molecules coumarins hydroxamic acids HDAC gene expression fluorescent probe docking analysis |
| title | Design of Fluorescent Coumarin-Hydroxamic Acid Derivatives as Inhibitors of HDACs: Synthesis, Anti-Proliferative Evaluation and Docking Studies |
| title_full | Design of Fluorescent Coumarin-Hydroxamic Acid Derivatives as Inhibitors of HDACs: Synthesis, Anti-Proliferative Evaluation and Docking Studies |
| title_fullStr | Design of Fluorescent Coumarin-Hydroxamic Acid Derivatives as Inhibitors of HDACs: Synthesis, Anti-Proliferative Evaluation and Docking Studies |
| title_full_unstemmed | Design of Fluorescent Coumarin-Hydroxamic Acid Derivatives as Inhibitors of HDACs: Synthesis, Anti-Proliferative Evaluation and Docking Studies |
| title_short | Design of Fluorescent Coumarin-Hydroxamic Acid Derivatives as Inhibitors of HDACs: Synthesis, Anti-Proliferative Evaluation and Docking Studies |
| title_sort | design of fluorescent coumarin hydroxamic acid derivatives as inhibitors of hdacs synthesis anti proliferative evaluation and docking studies |
| topic | coumarins hydroxamic acids HDAC gene expression fluorescent probe docking analysis |
| url | https://www.mdpi.com/1420-3049/25/21/5134 |
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