Discovery of 4-Anilinofuro[2,3-b]quinoline Derivatives as Selective and Orally Active Compounds against Non-Small-Cell Lung Cancers

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• 作者：Yu-Wen Chen ; Yeh-Long Chen ; Chih-Hua Tseng ; Chih-Chung Liang ; Chia-Ning Yang ; Yun-Chin Yao ; Pei-Jung Lu ; Cherng-Chyi Tzeng
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：July 14, 2011
• 年：2011
• 卷：54
• 期：13
• 页码：4446-4461
• 全文大小：1268K
• 年卷期：v.54,no.13(July 14, 2011)
• ISSN：1520-4804

文摘

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 (13a) is selectively active against the growth of NCI-H460 and is highly water-soluble (63 渭g/mL). Its hydrochloride salt, 13a路HCl exhibited not only excellent water solubility (1049 渭g/mL) but also a high oral bioavailability (57.1%). Compound 13a may cause cancer cell apoptosis through inducing mitotic arrest and mitotic catastrophe mechanism. Xenographic studies indicated the tumor size with 13a路HCl treated nude mice was significantly lower than control. Further evaluation in an orthotopic lung cancer model indicated that 13a路HCl can be absorbed readily through oral administration, distributed to lung tissue, and exhibited significant efficacy in inhibiting the growth of lung cancers.