| 摘要: | Combretastatin A-4（簡稱CA-4），從南非一種柳樹Combretum caffrum（African Willow tree）的樹皮中分離出來。其結構類似colchicine的結構，對微小管的聚合有抑制效果，根據細胞毒殺測試顯示可以對抗多種人類癌細胞，被視為一種有潛力的抗有絲分裂藥物。目前combretastatin A-4衍生物及其抗癌活性已被廣泛地研究，而其水溶性的磷酸鈉鹽(CA-4P)已應用於臨床試驗階段。Combretastatin 衍生物的結構分析指出，其兩個芳香環cis構型對於細胞毒殺測試有較強的效果；然而cis構型容易轉變成trans構型，但trans構型會減低其對癌細胞生長及微管聚合的抑制作用。因此一些相關研究報導合成五環或六環來固定成cis構型。在本文研究中，使用isoxazole環來固定CA-4結構中 cis雙鍵的構型，製備一系列4,5-diarylisoxazole (8a-l)的CA-4衍生物並測試對卵巢癌細胞株、肝臟癌細胞株及子宮上皮癌細胞株的活性。其中8e是最有潛力的化合物，IC50分別為0.022 nM、0.065 nM和0.135 nM。
The combretastatin A-4 (CA-4), a natural product isolated from Combretum caffrum, has been found as a potent antimitotic agent. CA-4 strongly inhibits the polymerization of tubulin by binding to the colchicine site, and it shows strong cytotoxicity against a variety of human cancer cells. Antimitotic agents related to CA-4 have attracted much attention in past decade. To date, many CA-4 analogues and their anticancer activity have been extensively studied. Its water-soluble derivative, sodium phosphate prodrug (CA-4P), is currently evaluated for clinical applications.
The structure–activity relationship analysis of the combretastatins indicates that the cis configuration of the two aromatic rings is important for strong cytotoxicity. However, during storage and administration cis-combretastatin analogues tend to isomerize to trans-form. The trans-form of these compounds shows a dramatic decrease in the inhibitory effects on cancer cell growth and tublin polymerization. Accordingly, a number of cis-restricted analogues of CA-4 were prepared using 1,2-substituted five memberd heterocycles such as imidazole, oxazole, tetrazole, thiazole, dioxolane, furanone, and oxazolone.
In our efforts to discover active antimitotic agents, we utilized isoxazole ring to mimic the cis-form of the double bond in CA-4. In this study, a series of 4,5-diarylisoxaoles (8a-l) were prepared and their anticancer activity were also evaluated against human cancer cell lines including human cervical epitheloid carcinoma (HeLa), human hepatocellular carcinoma (HepG2), and human ovarian adenocarcinoma (OVCAR-3). Among them, 8e showed the most cytotoxicity with the IC50 value of 0.022~0.135 nM against three cancer cell lines. |
