Chemical Synthesis and Biological Activities of Amaryllidaceae Alkaloid Norbelladine Derivatives and Precursors

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.

Unveiling Amaryllidaceae alkaloids: from biosynthesis to antiviral potential – a review

“…In 2022, we studied the anti-DENV activity of norbelladine, its derivatives and its precursors. 3 We revealed that the 3,4dihydroxybenzaldehyde (selectivity index (SI) = 7.2), 3 ′ ,4 ′ -Odimethylnorbelladine (SI = 4.8), 4 ′ -O-methylnorbelladine (SI > 4.9), 3 ′ -O-methylnorbelladine (SI > 4.5), and norcraugsodine (SI = 3.2) reduced DENV infection with EC 50 values ranging from 24.1 to 44.9 mM, and the mechanism of action is currently under investigation. Barbosa et al searched for plant-derived antiviral agents against DENV and ZIKV.…”

“…the relative relevance of lycorine inhibition of correct viral polyprotein translation or nucleocapsid assembly on viral inhibition, has not been measured directly, which will be crucial to verify the importance of each pharmacophore. 3 (2) Cherylline non-methylated 3 ′ OH (compared to gigantelline), and the absence of hydroxyl group on the phenol cycle C3 (compared to gigantellinine) is required for its anti-viral activity specific to RNA replication (PDB: 5WZ3). 5 (3) Lycorine C1 hydroxyl group interacts with Zika virus RNA-dependent RNA polymerase to block RNA synthesis, (as shown by in vitro enzyme assay, docking evidence, and interaction with His110).…”

“…In less studied ring types, 3′,4′- O -dimethylnorbelladine methyl groups increased anti-DENV activity compared to single-methylated O -norbelladine, suggesting a key role played by these two functional groups in its interaction with its target although not yet characterized. 3 In contrast, norcraugsodine O -methylation abolished its anti-DENV potential and reduced its cytotoxicity, indicating the structure–activity relationship of norbelladine-type alkaloids.…”

“…122 Lycorine was shown to inhibit EV71 replication in cellulo and in animal models in previous studies. 123 In 2019, Wang et al showed that a lycorine derivative LY-55 (2-hydroxy-2,3a1,4,5,7,12b-hexahydro-1H- [1,3] dioxolo [4,5-j]pyrrolo[3,2,1-de]phenanthridin-1-yl 2-((4-uorophenyl)thio)acetate hydrochloride) inhibited EV71 and CVA16 with EC 50 ranging from 1.69 to 5.02 mM, and TC 50 of 106.36 mM 7 (Table 1). They determined that LY-55 inhibited the autophagy induced by the two viruses and was required for their replication.…”

“…(1) Haemanthamine structural conformation of C11 hydroxyl and C3 methoxy groups are required for DENV inhibition. 1 3 ′ ,4 ′ -O-Dimethylnorbelladine methyl groups increased anti-DENV activity 3. (2) Cherylline non-methylated 3 ′ OH (compared to gigantelline), and the absence of hydroxyl group on the phenol cycle C3 (compared to gigantellinine) is required for its anti-viral activity specific to RNA replication (PDB: 5WZ3) 5.…”