- 學位論文
臺灣產番荔枝科乙醯生合成物與其抗癌作用機轉之探討
The Studies of Acetogenins from Formosan Annonaceous Plants and the Mechanism of Their Anti-Cancer Action
摘要
癌症長期以來一直為人類疾病死亡因素之首。即使是現今醫藥發達的時代，人類仍未能找尋出有效的方法治療它。自藥用植物或民間常用草藥中尋求對抗疾病之藥用成分，長久以來一直為藥物化學家或天然物研究學者努力的目標。番荔枝科植物自古以來即被用為治療膿瘍、咳嗽、驅蟲、腹瀉、癲癇及腫瘤等民間用藥。近幾年來，在第一個番荔枝科乙醯生合成物 (annonaceous acetogenins) 的分離後，其強烈的殺蟲能力以及細胞毒性，更吸引了天然物化學家的注意。本研究延續對台灣產番荔枝科植物 (Formosan Annonaceous Plants) 抗腫瘤之活性成分物質的開發與研究，在相關活性導引分離法的配合下，我們從臺灣產番荔枝科植物：瓣立樓林果(Rollinia mucosa)之未成熟果實中純化獲得十九個番荔枝科乙醯生合成物 (四個新化合物)，山刺番荔枝(Annona montana)之種子甲醇萃取物中純化獲得到的三十八個番荔枝科乙醯生合成物(十四個新化合物)，以及自番荔枝(Annona squamosa)之未成熟果實中獲得七個番荔枝科乙醯生合成物(二個新化合物)，經由光譜分析和配合衍生物之製備，加以證明及確認其結構式，已完全確定結構的有六十一個，其中包含一個新骨架的乙醯生合成物 (19) 以及十九個新化合物 (8, 12, 18, 26, 27, 28, 29, 31, 36, 37, 42, 43, 46, 47, 48, 51, 52, 58 和 59)。這些化合物一方面進行細胞毒殺等初步的活性篩選，以從這些活性篩選中建立了活性結構的相對關係，且進一步進行藥理作用機轉的探討(細胞凋亡、鈣離子輸送），初步發現部分此類化合物具有螯合鈣離子的能力而提昇癌細胞毒殺的效果。
並列摘要
Cancer is still a serious disease for people worldwide. Although modern medical technology is far advance, no good solution is available to cure this widespread disease. Thus, the need for new antitumor drugs has become increasingly important. Our laboratory has discovered a series of compounds, Annonaceous acetogenins, from the plants of family, Annonaceae. These compounds generally possessed significant in vitro potency against cancer cell lines, and even some of them showed selectivity against the hepatoma cancer cells, Hep G2, and 2,2,15 and human ovarian cancer cells,1A9. The goal of this research work is to increase the potency and selectivity of these compounds as antitumor agents. The quest for bioactive natural products from Formosan Annonaceous plants led to the isolation of 61 Annonaceous acetogenins, including 19 compounds from the extracts of the unripe fruit of Rollinia mucosa (4 new compounds), 35 compounds from the seeds of Annona montana (14 new compounds), and 7 compounds from the unripe fruit of A. squamosa (2 new compounds). Among them, rollicosin (19) was a new skeleton of Annonaceous acetogenins and compounds 8, 12, 18, 26, 27, 28, 29, 31, 36, 37, 42, 43, 46, 47, 48, 51, 52, 58, and 59 were identified as new compounds. In addition to the primary goal, we made an attempt to elucidate the mechanism of anti-cancer action. The results of this research program will be useful for the rational development of Annonaceous acetogenins as candidates of antitumor agents.