斑蝥胺素、斑蝥亞胺素及其相關衍生物合成與細胞毒性之探討

Syntheses and Cytotoxic Effects of Cantharidin – imide, Cantharidin – imine and Relative Analogs

黃忠弘(Chung-Hung Huang)

指導教授 ： 林本元

臺北醫學大學/藥學院/藥學研究所/碩士(2007年)

摘要

斑蝥為翹翅目莞青科斑莞青屬的昆蟲，抵禦外敵時由腳關節處分泌之有毒物質，即為斑蝥素（Cantharidin；exo,exo-2,3-dimethyl-7-oxabicyclo〔2,2,1〕heptane-2,3-dicarboxylic anhydride)，又稱為西班牙蒼蠅。在國外的研究中，斑蝥素具有抗癌，或當除草劑、殺蟲劑、毛髮生長刺激劑及治療傳染性疣等效果。基於改善斑蝥素抗癌療效的目的，本研究進行斑蝥素之化學修飾，利用兩種不同方法合成出五種系列的斑蝥素衍生物，並進一步作細胞毒性評估。本實驗主要是以斑蝥素為原料與含一級氨取代物之化合物如磺胺系列、雜環系列和烷基雙胺系列，利用兩種不同方法合成所得出四種系列衍生物，其方法分別為：一是利用鹼性條件下高溫（約200℃)封管反應兩小時，冷卻後進行脫水反應；另一是利用無水酒精當溶劑高溫（約140℃)下封管反應四小時，最後都利用薄層層析法（TLC)純化，可分別得斑蝥胺素（Cantharidinimide)與斑蝥亞胺素（Cantharidinimine)之衍生物。除此之外，為了證實斑蝥亞胺素的結構，本實驗是將所得斑蝥亞胺素之衍生物利用硼氫化鈉在室溫下進行還原反應二十四小時，得到另一系列含二級氨基衍生物。合成的斑蝥胺素、斑蝥亞胺素與已還原斑蝥亞胺素衍生物，經過核磁共振儀、紅外光光譜儀和高解析度質譜儀確定結構，並進行細胞毒性評估。

關鍵字

斑蝥素 ； 斑蝥胺素 ； 斑蝥亞胺素 ； 細胞毒性

並列摘要

Mylabris phalerata, Meloidae family of Coleoptera, has been known since antiquity to produce a potent toxic defensive agent, now known as cantharidin （exo,exo-2,3-dimethyl-7-oxabicyclo〔2.2.1〕heptane-2,3-dicarboxylic anhydride), but more infamously known as Spanish Fly. In the past, Cantharidin has used as anticancer, herbicidal, pesticide, hair-growth stimulator and treatment of molluscum contagiosum activities. In order to study the cytotoxic effects of related compounds, we synthesized four series of cantharidinimides and cantharidinimines by the following two methods：Cantharidin with various primary amines were not only heated to 200℃ in miui-reactor for two hours, but also heated to 140℃ in the miui-reactor for four hours. Furthermore, because of proving the latter structure we used catharidinimine and sodium borohydride in the reductive reaction to obtain amino-containing derivatives. All of the cantharidinimides, cantharidinimines and relative derivatives were identified by 1H-NMR, IR and mass spectrometry, respectively. Moreover, we would try to evaluate cytotoxic effects of cantharidinimide, cantharidinimine and relative derivatives.

並列關鍵字

cantharidin ； cantharidinimide ； cantharidinimine ； cytotoxicity

參考文獻

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