| 摘要: | Combretastatin A-4 (CA-4)於1982年由Pettit教授等人由南非柳樹Combretum caffrum的樹皮部分分離出一種和秋水仙素(colchicine)同樣具有antitubulin活性的化合物，研究指出其與秋水仙素的結構類似且具有更強的抑制活性，並發現cis 結構對其抑制活性為非常重要的因子。
而後Pettit等人利用人工合成的方式得到了兩個化合物phenstatin與hydroxyphenstatin，此二者利用carbonyl group的sp2鍵結，使結構形成quasi “cis”的構形，因而同樣具有高度的抑制活性。
任職於國家衛生研究院的謝興邦研究員也針對 phenstatin的相關研究發表了數篇論文，他將phenstatin的結構中存在的hydroxy group以amino group取代，發現同樣具有高度的抑制活性，而且極易製成胺鹽，有助於藥劑的研發生產並增加人體對藥劑的吸收度，而後他合成出一系列含indole環的phenstatin類似物，發現其中數個具有全面性優於CA-4活性的化合物。
由於對抗癌藥物研究的興趣，本論文以isoquinoline環為基本骨架並適當地導入不同的取代基，合成出一系列1-aroylisoquinoline的phenstatin衍生物SIH6c、SIH7c、SIH6d、SIH7d。此外，我們也以3,4-dihydroisoquinoline為基本骨架合成出一系列1-aryl-3,4-dihydroisoquinoline衍生物SIH8a、SIH8b、SIH8c、SIH8d、SIH12b、SIH12c、SIH12e、SIH12f、SIH13，並以人類子宮頸癌上皮細胞(HeLa)、人類肝癌細胞(HepG2)與人類卵巢癌細胞(OVCAR-3)三種細胞株進行細胞毒殺活性的測試。結果顯示以SIH7c具有最強的細胞毒殺活性，CD50為0.05~0.3g/mL。
In 1982, combretastatin A-4 (CA-4) was isolated from the bark of the South African tree Combretum caffrum. CA-4 showed strong cytotoxicity against a variety of human cancer cells and was determined to be a potent antimitotic agent. CA-4 also exhibited antitubulin activity which binds to tubulin on the colchicine binding site.
Because CA-4 is currently the simplest structure for a natural product that binds to tubulin, a number of structure-activity relationship (SAR) have been reported. These studies indicate that the cis orientation of the two aromatic rings is the most important factor for the inhibition of cancer cell growth. Recently, two new benzophenones, phenstatin and hydroxyphenstatin were synthesized by Pettit’s group. Both of them showed potent anticancer and antimitotic activities comparable to CA-4. Replacement of double bond in CA-4 by a sp2-hybridized carbonyl group in phenstatin resulted in similar activity, which suggested that the two aryl rings in a quasi “cis” orientation appear to be necessary for strong cytotoxicity.
In this thesis, a series of 1-aroylisoquinoline and 1-aryl-3,4-dihydro-isoquinoline analogues (SIH6c, SIH7c, SIH6d, SIH7d, SIH8a, SIH8b, SIH8c, SIH8d, SIH12b, SIH12c, SIH12e, SIH12f and SIH13) were prepared and their cytotoxic activity were also evaluated against human cancer cell lines including human cervical epitheloid carcinoma, human hepatocellular carcinoma, and human ovarian adenocarcinoma. Among them, SIH7c showed the most cytotoxicity with CD50 values 0.05~0.3 g/mL against three cancer cell lines. |
