Chemical Synthesis and Biological Activities of Amaryllidaceae Alkaloid Norbelladine Derivatives and Precursors
Amaryllidaceae alkaloids (AAs) are a structurally diverse family of alkaloids recognized for their many therapeutic properties, such as antiviral, anti-cholinesterase, and anticancer properties. Norbelladine and its derivatives, whose biological properties are poorly studied, are key intermediates r...
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MDPI AG
2022-08-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/27/17/5621 |
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| author | Marie-Pierre Girard Vahid Karimzadegan Marianne Héneault Francis Cloutier Gervais Bérubé Lionel Berthoux Natacha Mérindol Isabel Desgagné-Penix |
| author_facet | Marie-Pierre Girard Vahid Karimzadegan Marianne Héneault Francis Cloutier Gervais Bérubé Lionel Berthoux Natacha Mérindol Isabel Desgagné-Penix |
| author_sort | Marie-Pierre Girard |
| collection | DOAJ |
| description | Amaryllidaceae alkaloids (AAs) are a structurally diverse family of alkaloids recognized for their many therapeutic properties, such as antiviral, anti-cholinesterase, and anticancer properties. Norbelladine and its derivatives, whose biological properties are poorly studied, are key intermediates required for the biosynthesis of all ~650 reported AAs. To gain insight into their therapeutic potential, we synthesized a series of <i>O</i>-methylated norbelladine-type alkaloids and evaluated their cytotoxic effects on two types of cancer cell lines, their antiviral effects against the dengue virus (DENV) and the human immunodeficiency virus 1 (HIV-1), and their anti-Alzheimer’s disease (anti-cholinesterase and -prolyl oligopeptidase) properties. In monocytic leukemia cells, norcraugsodine was highly cytotoxic (CC<sub>50</sub> = 27.0 μM), while norbelladine was the most cytotoxic to hepatocarcinoma cells (CC<sub>50</sub> = 72.6 μM). HIV-1 infection was impaired only at cytotoxic concentrations of the compounds. The 3,4-dihydroxybenzaldehyde (selectivity index (SI) = 7.2), 3′,4′-<i>O</i>-dimethylnorbelladine (SI = 4.8), 4′-<i>O</i>-methylnorbelladine (SI > 4.9), 3′-<i>O</i>-methylnorbelladine (SI > 4.5), and norcraugsodine (SI = 3.2) reduced the number of DENV-infected cells with EC<sub>50</sub> values ranging from 24.1 to 44.9 μM. The <i>O</i>-methylation of norcraugsodine abolished its anti-DENV potential. Norbelladine and its <i>O</i>-methylated forms also displayed butyrylcholinesterase-inhibition properties (IC<sub>50</sub> values ranging from 26.1 to 91.6 μM). Altogether, the results provided hints of the structure–activity relationship of norbelladine-type alkaloids, which is important knowledge for the development of new inhibitors of DENV and butyrylcholinesterase. |
| first_indexed | 2024-03-10T01:30:03Z |
| format | Article |
| id | doaj.art-c2c723e507d64a1894908f7a0266d136 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T01:30:03Z |
| publishDate | 2022-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-c2c723e507d64a1894908f7a0266d1362023-11-23T13:45:08ZengMDPI AGMolecules1420-30492022-08-012717562110.3390/molecules27175621Chemical Synthesis and Biological Activities of Amaryllidaceae Alkaloid Norbelladine Derivatives and PrecursorsMarie-Pierre Girard0Vahid Karimzadegan1Marianne Héneault2Francis Cloutier3Gervais Bérubé4Lionel Berthoux5Natacha Mérindol6Isabel Desgagné-Penix7Département de Chimie, Biochimie et Physique, Université du Québec à Trois-Rivières, Trois-Rivières, QC G8Z 4M3, CanadaDépartement de Chimie, Biochimie et Physique, Université du Québec à Trois-Rivières, Trois-Rivières, QC G8Z 4M3, CanadaDépartement de Chimie, Biochimie et Physique, Université du Québec à Trois-Rivières, Trois-Rivières, QC G8Z 4M3, CanadaDépartement de Chimie, Biochimie et Physique, Université du Québec à Trois-Rivières, Trois-Rivières, QC G8Z 4M3, CanadaDépartement de Chimie, Biochimie et Physique, Université du Québec à Trois-Rivières, Trois-Rivières, QC G8Z 4M3, CanadaDépartement de Biologie Médicale, Université du Québec à Trois-Rivières, Trois-Rivières, QC G8Z 4M3, CanadaDépartement de Chimie, Biochimie et Physique, Université du Québec à Trois-Rivières, Trois-Rivières, QC G8Z 4M3, CanadaDépartement de Chimie, Biochimie et Physique, Université du Québec à Trois-Rivières, Trois-Rivières, QC G8Z 4M3, CanadaAmaryllidaceae alkaloids (AAs) are a structurally diverse family of alkaloids recognized for their many therapeutic properties, such as antiviral, anti-cholinesterase, and anticancer properties. Norbelladine and its derivatives, whose biological properties are poorly studied, are key intermediates required for the biosynthesis of all ~650 reported AAs. To gain insight into their therapeutic potential, we synthesized a series of <i>O</i>-methylated norbelladine-type alkaloids and evaluated their cytotoxic effects on two types of cancer cell lines, their antiviral effects against the dengue virus (DENV) and the human immunodeficiency virus 1 (HIV-1), and their anti-Alzheimer’s disease (anti-cholinesterase and -prolyl oligopeptidase) properties. In monocytic leukemia cells, norcraugsodine was highly cytotoxic (CC<sub>50</sub> = 27.0 μM), while norbelladine was the most cytotoxic to hepatocarcinoma cells (CC<sub>50</sub> = 72.6 μM). HIV-1 infection was impaired only at cytotoxic concentrations of the compounds. The 3,4-dihydroxybenzaldehyde (selectivity index (SI) = 7.2), 3′,4′-<i>O</i>-dimethylnorbelladine (SI = 4.8), 4′-<i>O</i>-methylnorbelladine (SI > 4.9), 3′-<i>O</i>-methylnorbelladine (SI > 4.5), and norcraugsodine (SI = 3.2) reduced the number of DENV-infected cells with EC<sub>50</sub> values ranging from 24.1 to 44.9 μM. The <i>O</i>-methylation of norcraugsodine abolished its anti-DENV potential. Norbelladine and its <i>O</i>-methylated forms also displayed butyrylcholinesterase-inhibition properties (IC<sub>50</sub> values ranging from 26.1 to 91.6 μM). Altogether, the results provided hints of the structure–activity relationship of norbelladine-type alkaloids, which is important knowledge for the development of new inhibitors of DENV and butyrylcholinesterase.https://www.mdpi.com/1420-3049/27/17/5621Amaryllidaceae alkaloidnorbelladinedengue virusanti-cholinesterasespecialized metabolism<i>O</i>-methylation |
| spellingShingle | Marie-Pierre Girard Vahid Karimzadegan Marianne Héneault Francis Cloutier Gervais Bérubé Lionel Berthoux Natacha Mérindol Isabel Desgagné-Penix Chemical Synthesis and Biological Activities of Amaryllidaceae Alkaloid Norbelladine Derivatives and Precursors Molecules Amaryllidaceae alkaloid norbelladine dengue virus anti-cholinesterase specialized metabolism <i>O</i>-methylation |
| title | Chemical Synthesis and Biological Activities of Amaryllidaceae Alkaloid Norbelladine Derivatives and Precursors |
| title_full | Chemical Synthesis and Biological Activities of Amaryllidaceae Alkaloid Norbelladine Derivatives and Precursors |
| title_fullStr | Chemical Synthesis and Biological Activities of Amaryllidaceae Alkaloid Norbelladine Derivatives and Precursors |
| title_full_unstemmed | Chemical Synthesis and Biological Activities of Amaryllidaceae Alkaloid Norbelladine Derivatives and Precursors |
| title_short | Chemical Synthesis and Biological Activities of Amaryllidaceae Alkaloid Norbelladine Derivatives and Precursors |
| title_sort | chemical synthesis and biological activities of amaryllidaceae alkaloid norbelladine derivatives and precursors |
| topic | Amaryllidaceae alkaloid norbelladine dengue virus anti-cholinesterase specialized metabolism <i>O</i>-methylation |
| url | https://www.mdpi.com/1420-3049/27/17/5621 |
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