Oxidation at C-16 enhances butyrylcholinesterase inhibition in lupane triterpenoids

• Published in: Bioorganic chemistry 2018-09, Vol.79, p.301-309
• Main Authors: Castro, María Julia, Richmond, Victoria, Faraoni, María Belén, Murray, Ana Paula
• Format: Article
• Language: English
• Subjects: Acetylcholinesterase - chemistry; Acetylcholinesterase - metabolism; Animals; Butyrylcholinesterase - chemistry; Butyrylcholinesterase - metabolism; Cholinesterase inhibitors; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; Dose-Response Relationship, Drug; Humans; Lupane derivatives; Molecular Docking Simulation; Molecular modeling; Molecular Structure; Oxidation-Reduction; Structure-Activity Relationship; Torpedo; Triterpenes - chemical synthesis; Triterpenes - chemistry; Triterpenes - pharmacology; Triterpenoids
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2018.05.012

[Display omitted] •A set of mono-, di- and tri-oxolupanes were prepared starting from calenduladiol and lupeol.•Selective inhibition of butyrylcholinesterase was observed for all the derivatives.•Kinetic study and molecular modeling were carried with the most potent inhibitors.•Oxidation at C-16 of the lupane skeleton improves the cholinesterase inhibition. A set of triterpenoids with different grades of oxidation in the lupane skeleton were prepared and evaluated as cholinesterase inhibitors. Allylic oxidation with selenium oxide and Jones’s oxidation were employed to obtain mono-, di- and tri-oxolupanes, starting from calenduladiol (1) and lupeol (3). All the derivatives showed a selective inhibition of butyrylcholinesterase over acetylcholinesterase (BChE vs. AChE). A kinetic study proved that compounds 2 and 9, the more potent inhibitors of the series, act as competitive inhibitors. Molecular modeling was used to understand their interaction with BChE, the role of carbonyl at C-16 and the selectivity towards this enzyme over AChE. These results indicate that oxidation at C-16 of the lupane skeleton is a key transformation in order to improve the cholinesterase inhibition of these compounds.