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 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 (CC 50 = 27.0 μM), while norbelladine was the most cytotoxic to hepatocarcinoma cells (CC 50 = 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 EC 50 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 (IC 50 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.