摘要
目的：光学活性（－）１甲基石杉碱甲的合成及其乙酰胆碱酯酶抑制活性的研究。方法：从光学纯的（５Ｓ，９Ｒ）５出发，经Ｗｉｔｉｇ反应和双键异构化得化合物６。用三甲基氯硅烷和碘化钠选择性脱保护得吡啶酮７后，用甲醇钠和碘甲烷选择性Ｎ甲基化得８，经酯水解、Ｃｕｒｔｉｕｓ重排和脱保护合成了光学活性１位氮上甲基取代的石杉碱甲类似物１１。结果：类似物１１的乙酰胆碱酯酶抑制活性低于石杉碱甲。结论：１甲基能影响类似物１１和蛋白活性之间形成氢键的作用，因此降低其抑制活性。
AIM: to study the synthesis and the acetylcholinesterase inhibitory activity of optically active (-)1methyl hyperzine A( 11 ). METHODS: The optically pure intermediate (+)(5S,9R) 5 was used as the starting material. Wittig olefination of 5Z , followed by isomerization of double bond afforded (E)(+) 6 . Selective deprotection of 6 WTBZ by Me3SiCl/NaI in acetonitrile produced pyridione compound (-) 7 , which was selectively Nmethylated by NaOMe/CH3I to give (+) 8 . Subsequently, the title compound (-) 11 was obtained by hydrolysis of ester (+) 8 , modified Curtius rearrangement of acid THZ 9 and deprotection of urethane (+) 10 . RESULTS: The acetylcholinesterase inhibitory activities of analogues 11STBZ was found to be much lower than that of natural huperzine A. CONCLUSION: 1Methyl group in analogue 11 may influence the formation of hydrogen bond between the ring nitrogen and the protein residue in the active site of the acetylcholinesterase.
出处
《药学学报》
CAS
CSCD
北大核心
1999年第6期434-438,共5页
Acta Pharmaceutica Sinica
基金
国家自然科学基金
