Discovery of an Orally Active and Liver-Targeted Prodrug of 5-Fluoro-2′-Deoxyuridine for the Treatment of Hepatocellular Carcinoma

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• 作者：Youmei Peng ; Wenquan Yu ; Ertong Li ; Jinfeng Kang ; Yafeng Wang ; Qinghua Yang ; Bingjie Liu ; Jingmin Zhang ; Longyu Li ; Jie Wu ; Jinhua Jiang ; Qingduan Wang ; Junbiao Chang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：April 28, 2016
• 年：2016
• 卷：59
• 期：8
• 页码：3661-3670
• 全文大小：475K
• 年卷期：0
• ISSN：1520-4804

文摘

We report a series of novel O-(substituted benzyl) phosphoramidate prodrugs of 5-fluoro-2′-deoxyuridine for the treatment of hepatocellular carcinoma. Through structure optimization, the o-methylbenzyl analog (1t) was identified as an orally bioavailable and liver-targeted lead compound. This lead prodrug is well-tolerated at a dose up to 3 g/kg in Kuming mice via oral administration. An efficacy study demonstrated that it possesses good inhibitory effect (61.67% and 72.50%, respectively) on tumor growth in a mouse xenograft model. A metabolism study in Sprague–Dawley rats suggested that 1t can release the desired 5′-monophosphate in the liver with high liver-targeting index.