Studies on analogues of huperzine A for treatment of senile dementia. VI. Asymmetric total synthesis of 14-nor-huperzine A and its inhibitory activity of acetylcholinesterase.
- Author:
Xu-chang HE
1
;
Geng-li YU
;
Dong-lu BAI
Author Information
- Publication Type:Journal Article
- MeSH: Acetylcholinesterase; metabolism; Alkaloids; Alzheimer Disease; drug therapy; Animals; Cholinesterase Inhibitors; chemical synthesis; pharmacology; therapeutic use; Erythrocyte Membrane; drug effects; enzymology; Molecular Conformation; Molecular Structure; Rats; Sesquiterpenes; chemical synthesis; chemistry; pharmacology; therapeutic use
- From: Acta Pharmaceutica Sinica 2003;38(5):346-349
- CountryChina
- Language:Chinese
-
Abstract:
AIMTo study asymmetric total synthesis of 14-nor-huperzine A 2 and its inhibitory activity on acetylcholinesterase.
METHODSHighly enantioselective synthesis of compound 5 from beta-keto-ester 3 and 2-methylene-1,3-propanediol diacetate 4 by palladium-catalyzed bicycloannulation was carried out using new chiral ferrocenylphosphine ligands, such as 10, 11, followed by regioselective double-bond migration to produce compound 6. Optically pure 6 was obtained after enantio-enrichment recrystallization. Then, according to similar procedures of huperzine A synthesis, the target compound 14-nor-huperzine A 2 was prepared. The inhibitory activity was tested with rat erythrocyte membrame acetylcholinesterase.
RESULTSThe inhibitory activity of synthetic (-)-14-nor-huperzine A was 8 fold less potent than that of (-)-huperzine A.
CONCLUSIONA hydrogen-bond between 14-methyl group of (-) huperzine A and the main-chain oxygen of His 440 is necessary for the highly acetylcholinesterase inhibitory activity of huperzine A.
