含胺基酸之斑蝥胺素衍生物與醯亞胺類胺基二唑類似物的合成與抗菌活性之探討

1. 含胺基酸之斑蝥胺素衍生物與醯亞胺類胺基二唑類似物的合成與抗菌活性之探討含胺基酸之斑蝥胺素衍生物與醯亞胺類胺基二唑類似物的合成與抗菌活性之探討 • 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)，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。近來有學者發現，某些具有醯亞胺-胜結構的化合物，可抑制革蘭氏陽性菌及陰性菌，而具平面結構的化合物、金剛烷及二唑皆有抗菌效果，所以我們此次實驗會探討其抗菌的活性。 • 本實驗主要是以斑蝥素為原料與含一級胺取代物之化合物包括：胺基酸系列、具平面結構之化合物、金剛烷，在鹼性條件下高溫 (約200 ℃) 封管反應兩小時，冷卻後進行脫水反應，利用薄層層析法 (TLC) 純化，可得一系列斑蝥胺素 (Cantharidinimide) 之衍生物；另外亦有使用酸酐系列與胺基二唑，藉由相同反應條件合成，得到一系列醯亞胺衍生物。 • 合成的斑蝥胺素衍生物及醯亞胺衍生物，經過核磁共振儀、紅外光光譜儀、高解析度質譜儀確定結構，並進行抗菌活性測試。結果顯示化合物13 (4-Anthracen-2-yl-2,6-dimethyl-10-oxa-4-aza-tricyclo [5.2.1.02,6]decane-3,5- dione) 對Staphylococcus及Bacillus有較好的抑制作用，但是效果仍未比Penicillin G好。

2. Synthesis and Antibacterial Activity of Cantharidin with various Amino acid and their Thiadiazolylimide Analogues • 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 and treatment of molluscum contagiosum activities. • The new analogues contain various amino acids attached to the carboxylic anhydride exhibit antibacterial activity. The compounds with triazole structure have been evaluated their antitubercular activity and the new adamantanyl derivatives have found to have antibacterial activity. In addition, some new 1,3,4-thiadiazoles containing isomeric pyridyl have been found to be active against both Gram-positive and Gram-negative bacteria. • We used cantharidin as a starting material to react with primary amine, series of amino acid, diaminotriazole and aminoadamantane, by heating 200℃ in sealed tube to form various cantharidinimide derivatives. Furthermore, we used anhydrides and aminothiadiazole in the same condition to obtain thiazolylimide derivatives. • We suppose that it might have some steric hindrance between bulky amino acids and 2,3-dimethyl group of cantharidin and gave low yields. And we found that higher polarity of amino acids didn’t react with cantharidin. • All of the cantharidinimide and thiazolylimide derivatives were measured by 1H-NMR, IR and mass spectrometry. Therefore, we would try to evaluate antibacterial activity of cantharidinimide and thiazolylimide derivatives. The results indicated that compound 13 (4-Anthracen-2-yl-2,6-dimethyl-10-oxa-4-aza-tricyclo[5.2.1.02,6]decane-3,5-dione) exhibits higher inhibitory activity against Staphylococcus and Bacillus than others, but is still less effective than penicillin G.