衍生自Pavine 架構之中樞神經藥物研發(II)

Abstract

由3D立體結構解析，化合物中氮及氧若有一定距離在擬副交感神經藥當中扮演一個重要的角色，如乙醯膽鹼酯酶抑制藥物，且這些藥物擁有在結構上相似的特徵但卻以不同的作用模式與藥物標的結合，因此在活性及選擇性的問題上有待改善。這些藥物在藥物化學與作用機轉方面是還有待釐清的領域。有鑑於此，本論文便針對於天然富含具anti-acetylcholinesterase初步活性之化合物，以適當的化學反應條件，合成出一些具有特殊架構的化合物以供日後藥理作用之研究。 本論文之目標化合物是以富含於厚殻桂(Cryptocaryachinensis)之pavine類生物鹼(-)-caryachine N-metho salt(1)、(-)-crychine(7)及得自文珠蘭之lycorine(15)當起始物而加以製備。其中四級銨鹽可經過三個步驟轉變成6R-Iodo-N,O-dimethyl-6 secocaryachine(5)，而從厚殻桂取得之三級胺藉由三步反應，可得到關鍵中間體之二級胺Dihydrosecocrychine (10)，分別是氮-苄基化反應、Hofmann degradation與催化性氫化反應(3°N → 4°N, 4°N → 3°N, 3°N →2°N)，接著化合物 10 再與二鹵烷進行氮-烷化反應(N-alkylation)，得一系列產物N,N-cycloethano salt (11a)；N,N-cyclobutano salt (11b)；N,N-cyclohaxano salt (11c) of dihydrosecocrychine (10)。另一得自文珠蘭之三級胺lycorine (15)經三個步驟可得到一芳香環化及氧化性產物 4,5-dihydrohippadine (18)。這些製備出的化合物之中樞神經作用，將以臨床用藥為對照組進一步探討。希望藉此建立結構活性關係而供往後之中樞神經藥物研究之參考。

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.