- 學位論文
4-苯胺基呋喃[2,3-b]喹啉衍生物之合成與抗癌活性評估
Synthesis and anticancer evaluation of 4-anilinofuro[2,3-b]quinoline derivatives
摘要
本實驗室合成一系列的4-苯胺呋喃[2,3-b]喹啉（4-anilinofuro[2,3-b]quinoline）衍生物並測試其抗增生活性，雖然有良好的活性，但這些化合物共同的缺點有：抗增生活性的選擇性（selective cytotoxicity）差、水溶解度（water solubility）低、口服生體可利用率(oral bioavailability)差等。因此，在4-苯胺呋喃[2,3-b]喹啉的衍生物中，我們發現(E)-1-(4-(呋喃[2,3-b]喹啉-4-基胺基)苯基)乙酮O-2-胺基乙基（(E)-1-(4-(furo[2,3-b]quinolin-4-ylamino) phenyl)ethanone O-2-aminoethyloxime）（17g）對於非小細胞肺癌細胞NCI-H460是具有明顯選擇性的抗增生活性及良好的水溶度（63 μg/mL）。化合物 17g．3 HCl 不僅具有高度的水溶度 (1049 μg/mL) 、良好的生體可利用率BA=57.1%（口服投藥）。化合物17g可藉由結合微管蛋白（tubulin）並且抑制微管蛋白聚合（tubulin polymerization）來誘發有絲分裂停滯（mitotic arrest）以及細胞凋亡（apoptosis）。因此，化合物17g非常有潛力成為高選擇性的非小細胞肺癌抑制劑。
並列摘要
We have reported the preparation and anticancer evaluation of certain 4-anilinofuro-[2,3-b]quinolines. However, drawbacks such as lack of selective cytotoxicity, poor oral bioavailability, and poor water solubility exhibited by these compounds prompted us to search for newer derivatives. Among them, (E)-1-(4-(furo[2,3-b]quinolin-4-ylamino) phenyl)ethanone O-2-aminoethyloxime (17g) is selectively active against the growth of NCI-H460 and is highly water-soluble (63 μg/mL). Its hydrochloride salt, 17g．3 HCl exhibited not only excellent water solubility (1049 μg/mL) but also a high oral bioavailability (57.1%). Compound 17g may cause cancer cell apoptosis through inducing mitotic arrest and mitotic catastrophe mechanism. Xenographic studies indicated the tumor size with 17g．3 HCl treated nude mice was significantly lower than control. Further evaluation in an orthotopic lung cancer model indicated that 17g．3HCl can be absorbed readily through oral administration, distributed to lung tissue, and exhibited significant efficacy in inhibiting the growth of lung cancers.
參考文獻
延伸閱讀
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