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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| Main Authors: | , , , , , , |
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| Format: | Book |
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MDPI AG,
2022-05-01T00:00:00Z.
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| Online Access: | Connect to this object online. |
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| Summary: | 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. |
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| Item Description: | 10.3390/ph15050585 1424-8247 |