Design, Semisynthesis, and Estrogenic Activity of Lignan Derivatives from Natural Dibenzylbutyrolactones
Based on molecular docking studies on the ERα, a series of lignan derivatives (<b>3</b>–<b>16</b>) were designed and semisynthesized from the natural dibenzylbutyrolactones bursehernin (<b>1</b>) and matairesinol dimethyl ether (<b>2</b>). To examine t...
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MDPI AG
2022-05-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/15/5/585 |
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| author | Priscila López-Rojas Ángel Amesty Miguel Guerra-Rodríguez Yeray Brito-Casillas Borja Guerra Leandro Fernández-Pérez Ana Estévez-Braun |
| author_facet | Priscila López-Rojas Ángel Amesty Miguel Guerra-Rodríguez Yeray Brito-Casillas Borja Guerra Leandro Fernández-Pérez Ana Estévez-Braun |
| author_sort | Priscila López-Rojas |
| collection | DOAJ |
| description | Based on molecular docking studies on the ERα, a series of lignan derivatives (<b>3</b>–<b>16</b>) were designed and semisynthesized from the natural dibenzylbutyrolactones bursehernin (<b>1</b>) and matairesinol dimethyl ether (<b>2</b>). To examine their estrogenic and antiestrogenic potencies, the effects of these compounds on estrogen receptor element (ERE)-driven reporter gene expression and viability in human ER+ breast cancer cells were evaluated. Lignan compounds induced ERE-driven reporter gene expression with very low potency as compared with the pure agonist E2. However, coincubation of 5 μM of lignan derivatives <b>1</b>, <b>3</b>, <b>4</b>, <b>7</b>, <b>8</b>, <b>9</b>, <b>11</b>, <b>13</b>, and <b>14</b> with increasing concentrations of E2 (from 0.01 pM to 1 nM) reduced both the potency and efficacy of pure agonists. The binding to the rhERα-LBD was validated by TR-FRET competitive binding assay and lignans bound to the rhERα with IC<sub>50</sub> values from 0.16 μM (compound <b>14</b>) to 6 μM (compound <b>4</b>). Induced fit docking (IFD) and molecular dynamics (MD) simulations for compound <b>14</b> were carried out to further investigate the binding mode interactions. Finally, the in silico ADME predictions indicated that the most potent lignan derivatives exhibited good drug-likeness. |
| first_indexed | 2024-03-10T03:09:25Z |
| format | Article |
| id | doaj.art-58ab08d216af458aa014a9b64bba7b9c |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-10T03:09:25Z |
| publishDate | 2022-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-58ab08d216af458aa014a9b64bba7b9c2023-11-23T12:34:56ZengMDPI AGPharmaceuticals1424-82472022-05-0115558510.3390/ph15050585Design, Semisynthesis, and Estrogenic Activity of Lignan Derivatives from Natural DibenzylbutyrolactonesPriscila López-Rojas0Ángel Amesty1Miguel Guerra-Rodríguez2Yeray Brito-Casillas3Borja Guerra4Leandro Fernández-Pérez5Ana Estévez-Braun6Departamento de Química Orgánica, Instituto Universitario de Bio-Orgánica, Universidad de La Laguna, Avda. Astrofísico Fco. Sánchez 2, 38206 La Laguna, Tenerife, SpainDepartamento de Química Orgánica, Instituto Universitario de Bio-Orgánica, Universidad de La Laguna, Avda. Astrofísico Fco. Sánchez 2, 38206 La Laguna, Tenerife, SpainInstituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS), Universidad de Las Palmas de Gran Canaria (ULPGC), Paseo Blas Cabrera Felipe s/n, 35016 Las Palmas de Gran Canaria, SpainInstituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS), Universidad de Las Palmas de Gran Canaria (ULPGC), Paseo Blas Cabrera Felipe s/n, 35016 Las Palmas de Gran Canaria, SpainInstituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS), Universidad de Las Palmas de Gran Canaria (ULPGC), Paseo Blas Cabrera Felipe s/n, 35016 Las Palmas de Gran Canaria, SpainInstituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS), Universidad de Las Palmas de Gran Canaria (ULPGC), Paseo Blas Cabrera Felipe s/n, 35016 Las Palmas de Gran Canaria, SpainDepartamento de Química Orgánica, Instituto Universitario de Bio-Orgánica, Universidad de La Laguna, Avda. Astrofísico Fco. Sánchez 2, 38206 La Laguna, Tenerife, SpainBased on molecular docking studies on the ERα, a series of lignan derivatives (<b>3</b>–<b>16</b>) were designed and semisynthesized from the natural dibenzylbutyrolactones bursehernin (<b>1</b>) and matairesinol dimethyl ether (<b>2</b>). To examine their estrogenic and antiestrogenic potencies, the effects of these compounds on estrogen receptor element (ERE)-driven reporter gene expression and viability in human ER+ breast cancer cells were evaluated. Lignan compounds induced ERE-driven reporter gene expression with very low potency as compared with the pure agonist E2. However, coincubation of 5 μM of lignan derivatives <b>1</b>, <b>3</b>, <b>4</b>, <b>7</b>, <b>8</b>, <b>9</b>, <b>11</b>, <b>13</b>, and <b>14</b> with increasing concentrations of E2 (from 0.01 pM to 1 nM) reduced both the potency and efficacy of pure agonists. The binding to the rhERα-LBD was validated by TR-FRET competitive binding assay and lignans bound to the rhERα with IC<sub>50</sub> values from 0.16 μM (compound <b>14</b>) to 6 μM (compound <b>4</b>). Induced fit docking (IFD) and molecular dynamics (MD) simulations for compound <b>14</b> were carried out to further investigate the binding mode interactions. Finally, the in silico ADME predictions indicated that the most potent lignan derivatives exhibited good drug-likeness.https://www.mdpi.com/1424-8247/15/5/585natural productslignansestrogenic and antiestrogenic activitiesinduced fit docking (IFD)molecular dynamics (MD) |
| spellingShingle | Priscila López-Rojas Ángel Amesty Miguel Guerra-Rodríguez Yeray Brito-Casillas Borja Guerra Leandro Fernández-Pérez Ana Estévez-Braun Design, Semisynthesis, and Estrogenic Activity of Lignan Derivatives from Natural Dibenzylbutyrolactones Pharmaceuticals natural products lignans estrogenic and antiestrogenic activities induced fit docking (IFD) molecular dynamics (MD) |
| title | Design, Semisynthesis, and Estrogenic Activity of Lignan Derivatives from Natural Dibenzylbutyrolactones |
| title_full | Design, Semisynthesis, and Estrogenic Activity of Lignan Derivatives from Natural Dibenzylbutyrolactones |
| title_fullStr | Design, Semisynthesis, and Estrogenic Activity of Lignan Derivatives from Natural Dibenzylbutyrolactones |
| title_full_unstemmed | Design, Semisynthesis, and Estrogenic Activity of Lignan Derivatives from Natural Dibenzylbutyrolactones |
| title_short | Design, Semisynthesis, and Estrogenic Activity of Lignan Derivatives from Natural Dibenzylbutyrolactones |
| title_sort | design semisynthesis and estrogenic activity of lignan derivatives from natural dibenzylbutyrolactones |
| topic | natural products lignans estrogenic and antiestrogenic activities induced fit docking (IFD) molecular dynamics (MD) |
| url | https://www.mdpi.com/1424-8247/15/5/585 |
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