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Chemical Synthesis and Biological Activities of Amaryllidaceae Alkaloid Norbelladine Derivatives and Precursors
Authors:Marie-Pierre Girard,Vahid Karimzadegan,Marianne Hé  neault,Francis Cloutier,Gervais Bé  rubé  ,Lionel Berthoux,Natacha Mé  rindol,Isabel Desgagné  -Penix
Affiliation:1.Département de Chimie, Biochimie et Physique, Université du Québec à Trois-Rivières, Trois-Rivières, QC G8Z 4M3, Canada;2.Département de Biologie Médicale, Université du Québec à Trois-Rivières, Trois-Rivières, QC G8Z 4M3, Canada
Abstract: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 O-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 (CC50 = 27.0 μM), while norbelladine was the most cytotoxic to hepatocarcinoma cells (CC50 = 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′-O-dimethylnorbelladine (SI = 4.8), 4′-O-methylnorbelladine (SI > 4.9), 3′-O-methylnorbelladine (SI > 4.5), and norcraugsodine (SI = 3.2) reduced the number of DENV-infected cells with EC50 values ranging from 24.1 to 44.9 μM. The O-methylation of norcraugsodine abolished its anti-DENV potential. Norbelladine and its O-methylated forms also displayed butyrylcholinesterase-inhibition properties (IC50 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.
Keywords:Amaryllidaceae alkaloid, norbelladine, dengue virus, anti-cholinesterase, specialized metabolism, O-methylation, galanthamine, Alzheimer’  s disease, antiviral
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