ABSTRACT
BACKGROUND: A new family of purine nucleoside cholinesterase inhibitors was disclosed by us, with potency and selectivity over acetylcholinesterase or butyrylcholinesterase controlled by tuning structural and stereochemical features of nucleosides with perbenzylated glycosyl moieties. OBJECTIVE: Design, synthesis, and biological evaluation of new purine nucleosides were used to investigate glycon protecting group pattern required for anticholinesterase activity and selectivity. METHODS: Regioselective chemistry to introduce methyl/benzyl groups in glycon donors and Nglycosylation was used to acquire the target nucleosides. Evaluation of their biological potential and selectivity as cholinesterase inhibitors was performed. RESULTS: Synthetic strategies chosen resulted in high glycon donor's overall yield and regio- and stereoselectivity was found in N-glycosylation reaction. Some of the new nucleosides are cholinesterase inhibitors and selectivity for butyrylcholinesterase was also achieved. CONCLUSION: N-glycosylation reaction was stereoselective for the ß-anomers while regioselectivity was achieved for the N9 isomers when glycon positions 2 and 3 were methylated. Cholinesterase inhibition was found when the 2,3-di-O-benzyl-4-O-methyl pattern is present in the sugar moiety. Amongst the new compounds, the two most promising ones showed micromolar inhibition (mixed inhibition), being one of them selective for butyrylcholinesterase inhibition.
Subject(s)
Butyrylcholinesterase , Cholinesterase Inhibitors , Cholinesterase Inhibitors/chemistry , Butyrylcholinesterase/metabolism , Purine Nucleosides/pharmacology , Acetylcholinesterase/metabolism , Nucleosides/chemistry , Structure-Activity RelationshipABSTRACT
Alzheimer's Disease (AD) is characterized by a progressive cholinergic neurotransmission imbalance, with a decrease of acetylcholinesterase (AChE) activity followed by a significant increase of butyrylcholinesterase (BChE) in the later AD stages. BChE activity is also crucial for the development of Aß plaques, the main hallmarks of this pathology. Moreover, systemic copper dyshomeostasis alters neurotransmission leading to AD. In the search for structures targeting both events, a set of novel 6-benzamide purine nucleosides was synthesized, differing in glycone configuration and N7/N9 linkage to the purine. Their AChE/BChE inhibitory activity and metal ion chelating properties were evaluated. Selectivity for human BChE inhibition required N9-linked 6-deoxy-α-d-mannosylpurine structure, while all three tested ß-d-derivatives appeared as non-selective inhibitors. The N9-linked l-nucleosides were cholinesterase inhibitors except the one embodying either the acetylated sugar or the N-benzyl-protected nucleobase. These findings highlight that sugar-enriched molecular entities can tune bioactivity and selectivity against cholinesterases. In addition, selective copper chelating properties over zinc, aluminum, and iron were found for the benzyl and acetyl-protected 6-deoxy-α-l-mannosyl N9-linked purine nucleosides. Computational studies highlight molecular conformations and the chelating molecular site. The first dual target compounds were disclosed with the perspective of generating drug candidates by improving water solubility.
ABSTRACT
Among marine organisms, sponges are the richest sources of pharmacologically-active compounds. Stemming from a previous lead discovery program that gathered a comprehensive library of organic extracts of marine sponges from the off-shore region of Portugal, crude extracts of Erylus cf. deficiens collected in the Gorringe Bank (Atlantic Ocean) were tested in the innovative high throughput screening (HTS) assay for inhibitors of indoleamine 2,3-dioxygenase (IDO) and showed activity. Bioassay guided fractionation of the dichloromethane extract led to the isolation of four new glycolipids, named erylusamide A-D. The structures of the isolated compounds were established by 1D and 2D nuclear magnetic resonance (NMR) spectroscopy, high-resolution electrospray ionization mass spectrometry (HR-ESI-MS) and chemical derivatization. The metabolites shared a pentasaccharide moiety constituted by unusual highly acetylated á´ -glucose moieties as well as á´ -xylose and á´ -galactose. The aglycones were unprecedented long chain dihydroxyketo amides. Erylusamides A, B and D differ in the length of the hydrocarbon chain, while erylusamide C is a structural isomer of erylusamide B.
Subject(s)
Glycolipids/chemistry , Animals , Atlantic Ocean , COS Cells/drug effects , Chlorocebus aethiops , Glycolipids/pharmacology , Porifera , Portugal , Structure-Activity RelationshipABSTRACT
2-O-Acyl protected-d-ribo-3-uloses reacted with [(ethoxycarbonyl)methylene]triphenylphosphorane in acetonitrile to afford regio- and stereoselectively 2-(Z)-alkenes in 10-60 min under microwave irradiation. This domino reaction is proposed to proceed via tautomerization of 3-ulose to enol, acyl migration, tautomerization to the 3-O-acyl-2-ulose, and Wittig reaction. Alternatively, in chloroform, regioselective 3-olefination of 2-O-pivaloyl-3-uloses gave (E)-alkenes, key precursors for the miharamycins' bicyclic sugar moiety.
