| Summary: | 碩士 === 國立臺灣大學 === 藥學研究所 === 97 === According to molecular modeling analysis, compounds which have characteristic linkage with definite distance between nitrogen and oxygen play an important role in the development of anti-acetylcholinesterase drugs. These drugs
possess similar structural characteristics but have different targets. Therefore, the issue of activity and selectivity of these drugs still remains to be verified. The pharmaceutical chemistry and the action mechanism of these drugs have not been explorded to a great extent. Based on these, this study aimed to modify the pharmacophores of the naturally abundant compounds exhibiting anti-acetylcholinesterase activity by unique appropriate chemical reactions to produce some unique compounds for further pharmacological study.
The target compounds used as starting material in this article are pavine alkaloid, including (-)-caryachine N-metho salt (1) and (-)-crychine (7) which are abundant in Cryptocarya chinensis Hemsl. and lycorine which is abundant in C.asiaticumvar. sinicum. (-)-caryachine N-metho salt (1) was converted into 6R-iodo-N,O-dimethyl-6 secocaryachine (5) via three steps. (-)-crychine (7) was
converted into the key intermediate dihydrosecocrychine (10) in three steps, including N-benzylation, Hofmann degradation and catalytic hydrogenation (3°N → 4°N, 4°N
→ 3°N, 3°N → 2°N). And also, N,N-cycloethano salt (11a), N,N-cyclobutano salt (11b) and N,N-cyclohaxano salt (11c) of dihydrosecocrychine (10) were prepared unexpectedly by reacting the secondary amine with 1,2-dihaloethane,
1,4-dihalobutane or 1,5-dihalopentane respectively. The lycorine (15), tertiary amine, from C. asiaticumvar. sinicum was converted into 4,5-dihydrohippadine (18) in three steps.
The activities of these prepared compounds need to be assayed by comparing with the clinically used drug, glanthamine as veritive control. Hopefully, from these studies some SAR will be drawn and the result will be served as a reference for further exploration.
|
|---|
