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Preparation and Bioactivity Study of Boldine and Litebamine Derivatives
|Advisor:||陳春雄(Chung-Hsiung Chen),李水盛(Shoei-Sheng Lee)|
boldine,aporphine alkaloid,litebamine,phenanthrene alkaloid,acetylcholinesterase,acetylcholinesterase inhibitory activity,
|Publication Year :||2007|
|Abstract:||波爾定鹼(Boldine, 1)為大量存在於杯軸花科(Monimiaceae)、樟科(Lauraceae)或木蘭科(Magnoliaceae)植物中的阿朴芬(aporphine)類生物鹼成分，文獻搜尋可得知其有多種生物活性作用。Litebamine (3)為樟科(Lauraceae)植物山胡椒(Litsea cubeba Persoon)的木部分離出，具有phenanthrene架構的生物鹼，經由生物活性篩選發現其具有抑制乙醯膽鹼酵素之活性。
分析結構發現，boldine (1)與litebamine (3) 結構上氧和氮原子之距離與乙醯膽鹼之乙醯基部份氧原子和膽鹼部分氮原子間相對原子距離類似，故此本論文在於製備這兩類生物鹼衍生物並進一步討論這類化合物之結構與抗乙醯膽鹼酵素活性的關係。
以boldine (1)為起始物，經簡易之半合成方法可大量製備litebamine (3)，接著分別在以boldine (1)及litebamine (3)經過酚基保護，催化性氫化反應，及接續之去甲基反應可得到phenanthrene架構去3, 7酚基衍生物(12)，此架構於C環飽和之去3, 7酚基衍生物(10, 11)，及C和D環皆飽和之衍生物(13, 14)；另外也得到aporphine架構去2, 9酚基的衍生物(16, 17, 19, 20)。
Boldine (1), an aporphine alkaloid, that is abundantly present in a number of plants of the families including Monimiaceae, Lauraceae and Magnoliaceae. Litebamine (3) is a phenanthrene alkaloid isolated from the wood of Litsea cubeba. It possesses inhibitory activity against acetylcholinesterase (AChE). Comparison of the structure of acetylcholine, boldine (1) and litebamine (3), we can found that the distance between N and O of these three molecules were similar and could act with AChE with similar mode. So the purpose of this thesis was to prepare the boldine (1) and litebamine (3) derivatives for exploration in their SAR with respect to AChE inhibitory activity.
Starting from boldine (1), litebamine (3) was prepared by a facile semisynthetic method. Following subsequently with three reaction steps on 3, protection of the phenolic function with phenyltetrazoyl group, catalytic hydrogenation to remove the phenyltetrazoyloxy group, and demethylation, five products (10-14) were prepared starting from litebamine (3). They are 3,7-didehydroxy-9,10-dihydrolitebamine (10), didehydroxy-O,O-didemethyl-9,10-dihydrolitebamine (11), didehydroxy-O,O-di-
demethyllitebamine (12), and didehydroxy-octahydrolitebamine (13, 14). Using boldine (1) as starting materials and via similar approaches, four products (16-17, 19-20) were yielded. They are 1,10-dimethoxyaporphine (16), 1,10-dihydroxyaporphine (17), 1,10-di-diethoxyethoxyaporphine (19), and 1-diethoxyethoxy-10-hydroxyaporphine (20).
The bioactivity of these products against acetylcholinesterase has been investigated. The results indicated that compound 16 has better inhibitory activity against AChE. The result, however, provide further informations regarding SAR of these two kinds of alkaloids.
|Appears in Collections:||藥學系|
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