- 學位論文
原金星蕨酮protoapigenone之合成製程改良及其黃酮類衍生物之合成設計研究
The improvement in manufacturing of protoapigenone and the synthetic design of its flavonoid derivatives
摘要
原金星蕨酮(protoapigenone)為自台灣特有種粗毛金星蕨(Thelypteris torresiana, Thelypteridaceae)中分離出之新型黃酮類化合物，經活體外細胞毒殺活性篩選(in vitro cytotoxicity screening)後發現此天然物不僅對於數種癌細胞株有優異之毒殺性，甚至可與臨床用藥物doxorubicin相比擬，為極具潛力之先導化合物(lead compound)。在先前生技製藥國家型計畫(NSTPBP)辦公室的協助下，原金星蕨酮已展開並完成數項臨床前試驗(pre-clinical tests)，然而為了符合後續更多相關測試的需求，此化合物必須有大量且穩定的提供來源。原金星蕨酮的全合成研究雖已完成，但總產率不高且在大量製備時遭遇了許多問題。本研究的目的在於對原金星蕨酮的合成設計進行改良。以市售的柚皮素 (naringenin)為起始物，經由碘的氧化後可以高產率且不經純化的方式得到芹素(apigenin)。而在微波(microwave)的協助及高價碘試劑的氧化下，便能得到原金星蕨酮。此法不僅將原本的六步反應縮短成兩步，也大大的提高了反應的總產率，在臨床前試驗的藥物提供上有相當大的助益。除了合成方法的改良外，我們也對如何快速提供黃酮類前驅物的方法進行研究，並開發了一條以冠醚(18-crown-6 ether)媒介的快速合環法來提供許多不同的黃酮類化合物，在結合前述之微波氧化反應後，便能進一步的對原金星蕨酮衍生物進行探討。最後，以結構與活性(structure-activity relationship，SAR)之觀點進行原金星蕨酮 4-喹諾酮類(4-quinolones)衍生物及 β-萘黃酮衍生物之合成研究，並由其中衍生出了一新型先導化合物 59l。目前此化合物為生技醫藥國家型計劃(NRPB, National Research Program for Biopharmaceuticals)之重點研究項目之一，相關之深入機轉探討及動物實驗也已展開。期待在結合不同領域之專家學者的合作下，能在原金星蕨酮系列衍生物中找出新型的抗癌藥物，對現今人類之醫學研究及疾病治療上盡一份心力。
並列摘要
Protoapigenone, a novel flavonoid isolated from the endemic fern of Taiwan (Thelypteris torresiana, Thelypteridaceae), possesses unique anti-tumor activity against several cancer cell lines that is even comparable to effect of the clinical drug doxorubicin. With the help of the National Science and Technology Program for Biotechnology and Pharmaceuticals (NSTPBP), several pre-clinical studies related to protoapigenone had begun, and some of them are completed recently. However, in order to support the need of every pre-clinical test, there must be a way to provide stable and large-scale sources of compounds. Although the original total synthetic study of protoapigenone has been accomplished, there are a lot of problems remain to be solved when it comes to a large-scale preparation. This study is aiming to modify the original synthetic method and provide a more efficient way to the scale-up condition. By using the commercial available naringenin as the starting material and iodine as the oxidizing agent, apigenin can be obtained with high yield without purification. After aids of microwave and hypervalent iodine reagents, protoapigenone is obtained with an improved yield in only two steps compared to the previous six-step reaction. This modification not only affords a higher total yield for the whole scheme but also greatly saves the time for the production of protoapigenone. Besides the modification of original synthetic scheme, this study also focuses on the research of flavone precursor synthesis and a useful crown-ether mediated cyclization strategy is developed. By combining the microwave-assisted oxidation, different protoapigenone derivatives will be synthesized efficiently. Finally, from the viewpoint of structure-activity relationship (SAR), the study of quinolones and β-naphthoflavone derivatives are also investigated. Among all the compounds synthesized, 59l exhibited the best in vitro activity and currently this compound is selected as one of the new lead candidates in the project of National Research Program for Biopharmaceuticals (NRPB). Now a series of pharmacology and animal studies about 59l have proceeded. We hope that through the cooperation of different scholars from different academic fields a new anti-cancer drug could be developed from 59l derivatives and make great contributions to the health of human beings.