斑蝥胺素及其類似衍生物合成與生物活性之研究

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斑蝥胺素及其類似衍生物合成與生物活性之研究 Study on the Synthesis and Bioactivity of Cantharidinimides and Their Analogues

中文摘要

斑蝥胺素及其類似衍生物合成及生物活性之研究

斑蝥素（Cantharidin; exo,exo-2,3-dimethyl-7-oxabicyclo[2.2.1] heptane-2,3-

dicarboxlic acid anhydride），為翹翅目、莞青科、斑莞青屬的昆蟲於抵禦外侮時所分泌的化合物，具有顯著的生物活性如引泡發赤、抗腫瘤劑、刺激毛髮及除草劑等作用。最近曾有研究指

出斑蝥素之N-衍生物類斑蝥胺具有一定的抗腫瘤效果且副作用較低。基於減少其毒性增加療效

的目的，本研究進行cantharidin 之化學修飾，合成系列之 N-衍生物，並進一步作生物活性評估。經由cantharidin 或其它酸酐衍生物與含胺基之取代物於高溫（約 200℃）在鹼性條件下封管加溫2 小時後，餾去溶媒純化後得到一系列之斑蝥胺素 N-衍生物（sulfa 和

ethanolamine 系列）。另外，藉由 Aziridine 的開環反應將反應物嘗試在不同的條件下經由位

向及之立體空間障礙的考量，合成另一系列衍生物。已合成的化合物，斑蝥素之N-衍生物及酸

酐素之N-衍生物，已由核磁共振儀、紅外線光譜儀、質譜儀和元素分析儀確定結構。此外也針對

sulfa 系列和 Aziridine 開環系列等產物在抗肝癌細胞 Hep 3B 的抑制性進行測試，而結果顯示化合物6 的抗肝癌細胞 Hep 3B 毒性最強，且優於斑蝥素。

英文摘要

Study on the Synthesis and Bioactivity of Cantharidinimides and Their Analogues Abstract

Cantharidin (exo,exo-2,3-dimethyl-7-oxabicyclo[2.2.1]heptane-2,3-dicarboxlic acid anhydride), is produced by beetles, belonging to the order of Coleotera, and family of Melodae, as a defense against predators. It has remarkable biological activity, and can be used as an acantholytic, an antitumor agent, a hair-growth stimulator and a pesticide.

It has been shown in animal studies that N-derivatives of cantharidin have certain inhibitory action on tumors with less side effects. Furthermore, in order to study the bioactivity and toxicity of related compounds, we synthesized a series of cantharidinimide by the following method: Cantharidin or other analogues were dealed with amino-containing substrate by heated to 200oC in a sealed tube for 2 hours. After cooling, the residuals were removed from the tube, and were further evaporated and purified by column chromatography (SiO2). Another series of N- cantharidinimide analogues were synthesized by the method of ring-opening of activated aziridine dealed with NaH at 80oC for 24 hours.

All of these cantharidinimides and their derivatives were measured by 1H-NMR, IR, mass spectrometry and elemental analysis. Besides, the series synthetic

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compounds of the sulfa and aziridine were tested for their capability to suppress growth of human hepatocellular carcinoma call line, Hep 3B. The results showed that compound 6 was the most potent, and it was more effective than cantharidin