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
傳統難溶性藥物的口服劑型設計傾向立即釋放系統，服用次數通常為一天三 次以上，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（ Can tharidinimide) 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。
Mylabris phalerata, Meloidae family of Coleoptera, has been known since antiquity to produce a potent toxic defensive agent, now known as canthari din （ exo,exo-2,3-dimethyl-7-oxabicyclo 〔 2.2.1 〕 heptane-2,3-dicarbo xylic anhydride), but more infamously known as Spanish Fly. In the past, Cantharidin has used as anticancer, herbicidal, pesticide, hair-growth stimu lator and treatment of molluscum contagiosum activities. In order to study t he cytotoxic effects of related compounds, we synthesized four series of ca ntharidinimides and cantharidinimines by the following two methods ： Ca ntharidin with various primary amines were not only heated to 200 in mi℃ ui-reactor for two hours, but also heated to 140 in the miui-reactor for fo℃ ur hours. Furthermore, because of proving the latter structure we used cath aridinimine and sodium borohydride in the reductive reaction to obtain ami no-containing derivatives. All of the cantharidinimides, cantharidinimines and relative derivatives were identified by 1H-NMR, IR and mass spectro metry, respectively. Moreover, we would try to evaluate cytotoxic effects o f cantharidinimide, cantharidinimine and relative derivatives.
Syntheses and Cytotoxic Effects of Cantharidin – imide, Cantharidin – imine and Relative Analogs
