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Synthesis and cholinesterase inhibiting potential of A-ring azepano- and 3-amino-3,4-seco-triterpenoids

Kazakova, Oxana ; Smirnova, Irina ; Lopatina, Tatyana ; Giniyatullina, Gul'nara ; Petrova, Anastasiya ; Khusnutdinova, Elmira ; Csuk, René ; Serbian, Immo ; Loesche, Anne

Bioorganic chemistry, 2020-08, Vol.101, p.104001-104001, Article 104001 [Periódico revisado por pares]

United States: Elsevier Inc

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Synthesis and cholinesterase inhibiting potential of A-ring azepano- and 3-amino-3,4-seco-triterpenoids
Autor: Kazakova, Oxana ; Smirnova, Irina ; Lopatina, Tatyana ; Giniyatullina, Gul'nara ; Petrova, Anastasiya ; Khusnutdinova, Elmira ; Csuk, René ; Serbian, Immo ; Loesche, Anne
Assuntos: Acetylcholinesterase ; Acetylcholinesterase - drug effects ; Alzheimer’s disease ; Animals ; Azepane ; Betulin ; Binding Sites ; Butyrylcholinesterase ; Butyrylcholinesterase - drug effects ; Cholinesterase Inhibitors - chemical synthesis ; Cholinesterase Inhibitors - chemistry ; Cholinesterase Inhibitors - pharmacology ; Electrophorus - metabolism ; Glycyrrhetinic acid ; Horses - blood ; Molecular Docking Simulation ; Oleanolic acid ; Triterpenes - chemical synthesis ; Triterpenes - chemistry ; Triterpenes - pharmacology ; Triterpenoids ; Ursolic acid
É parte de: Bioorganic chemistry, 2020-08, Vol.101, p.104001-104001, Article 104001
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SourceType-Scholarly Journals-1
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Descrição: [Display omitted] •A series of A-ring azepano- and 3-amino-3,4-seco-triterpenoids has been synthesized.•The compounds were screened for their biological activity in Ellman’s assays.•Azepanes proved to be good inhibitors for butyrylcholinesterase.•Reasonably high docking scores for BChE were obtained.•Azepanes 1, 7, 8, 12 and 18 were approximately 4 to 10 times more active than galantamine. In this study, a series of A-ring azepano- and 3-amino-3,4-seco-derivatives were synthesized from betulin, oleanolic, ursolic and glycyrrhetinic acids aiming to develop new cholinesterase inhibitors. Azepanobetulin, azepanoerythrodiol and azepanouvaol were modified to give amide and tosyl derivatives, while azepano-anhydrobetulines and azepano-glycyrrhetols were obtained for the first time. Oleanane and ursane type 3-amino-3,4-seco-4(23)-en triterpenic alcohols were synthesized by reducing the corresponding 2-cyano-derivatives accessible from Beckmann type 2 rearrangements. The compounds were screened in colorimetric Ellman’s assays to determine their ability to act as inhibitors for the enzymes acetylcholinesterase (AChE, from electric eel) and butyrylcholinesterase (BChE, from equine serum). While most of these compounds were only moderate inhibitors for AChE, several of them were shown to be inhibitors for BChE acting as mixed-type inhibitors. Azepanobetulin 1, its C28-amide derivatives 7 and 8, azepano-11-deoxo-glycyrrhetol 12 and azepanouvaol 18 held inhibition constants Ki ranging between 0.21 ± 0.06 to 0.68 ± 0.19 μM. Thus, they were approximately 4 to 10 times more active than standard galantamine hydrobromide. For all of the compounds reasonably high docking scores for BChE were obtained being in good agreement with the experimental results from the enzymatic studies. As a result, A-ring azepano-triterpenoids were found to be new scaffolds for the development of BChE inhibitors.
Editor: United States: Elsevier Inc
Idioma: Inglês

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Synthesis and cholinesterase inhibiting potential of A-ring azepano- and 3-amino-3,4-seco-triterpenoids

Kazakova, Oxana ; Smirnova, Irina ; Lopatina, Tatyana ; Giniyatullina, Gul'nara ; Petrova, Anastasiya ; Khusnutdinova, Elmira ; Csuk, René ; Serbian, Immo ; Loesche, Anne

United States: Elsevier Inc

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