Synthesis and biological evaluation of lycorine derivatives as dual inhibitors of humanacetylcholinesterase and butyrylcholinesterase

Abstract

BackgroundAlzheimer’s disease (AD) is a neurologically degenerative disorder that affects more than 20 million people worldwide. The selective butyrylcholinesterase (BChE) inhibitors and bivalent cholinesterase (ChE) inhibitors represent new treatments for AD.FindingsA series of lycorine derivatives (1–10) were synthesized and evaluated for anti-cholinesterase activity. Result showed that the novel compound 2-O-tert-butyldimethylsilyl-1-O-(methylthio)methyllycorine (7) was a dual inhibitor of human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBChE) with IC50 values of 11.40 ± 0.66 μM and 4.17 ± 0.29 μM, respectively. The structure-activity relationships indicated that (i) the 1-O-(methylthio)methyl substituent in lycorine was better than the 1-O-acetyl group for the inhibition of cholinesterase; (ii) the acylated or etherified derivatives of lycorine and lycorin-2-one were more potent against hBChE than hAChE; and (iii) the oxidation of lycorine at C-2 decreases the activity.ConclusionAcylated or etherified derivatives of lycorine are potential dual inhibitors of hBChE and hAChE. Hence, further study on the modification of lycorine for ChE inhibition is necessary.

Effect of lycorine on the structure and function of hepatoma cell membrane in vitro and in vivo

“…The cell membrane integrity of the lycorine group was negatively correlated with the dose (p < 0.01). It has been verified by the previous experimental results that the sialic acid content on the tumor cell membrane was reduced, and the integrity of the tumor cell membrane was indeed regulated by the sialic acid content on the tumor cell membrane [28].…”

Lycorine: A prospective natural lead for anticancer drug discovery

“…Lycorine series of Amaryllidaceae alkaloids require a hydrogen-bond acceptor at the C-1 for acetylcholinesterase and butyrylcholinesterase inhibitory activity and the lipophilic substituent at C-2 increases the activity. However, oxidation at C2 is supposed to deactivate the compound of its inhibitory effect [131,132]. The common structural Inactive [23] characteristics need for the pharmacologic activity of lycorine derivatives include, the planarity of the molecule, basic nitrogen, and free hydroxyl group.…”

Nature as a source of metabolites with cholinesterase-inhibitory activity: an approach to Alzheimer's disease treatment

“…However, modification of the lycorine skeleton by acetylation may increase the inhibitory potency (1‐ O ‐acetyllycorine, IC 50 = 0.96 μ m ) . The hydrogen‐bond acceptor at the C1 of lycorine is needed for AChE inhibition, while a lipophilic substituent at C2 increases the inhibitory activity . A recent work involving lycorine derivatives showed that acylation or etherification of lycorine produces compounds able to inhibit both human BuChE (IC 50 = 4–20 μ m ) and AChE (IC 50 = 11–50 μ m ) …”

“…[96] The hydrogen-bond acceptor at the C1 of lycorine is needed for AChE inhibition, while a lipophilic substituent at C2 increases the inhibitory activity. [97] A recent work involving lycorine derivatives showed that acylation or etherification of lycorine produces compounds able to inhibit both human BuChE (IC50 = 4-20 mm) and AChE (IC50 = 11-50 mm). [97] Other groups of alkaloids have been studied, but without great anti-ChE activity as compared with those mentioned above.…”

“…[97] A recent work involving lycorine derivatives showed that acylation or etherification of lycorine produces compounds able to inhibit both human BuChE (IC50 = 4-20 mm) and AChE (IC50 = 11-50 mm). [97] Other groups of alkaloids have been studied, but without great anti-ChE activity as compared with those mentioned above. Natural lycopodane-type alkaloids, such as lycodoline or lycofoline, inhibit AChE at concentrations ranging from 191 to >2000 mm but the majority of these compounds do not inhibit BuChE (IC50 > 2000 mm).…”