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

作者：Peng, Youmei; Yu, Wenquan; Li, Ertong; Kang, Jinfeng; Wang, Yafeng; Yang, Qijughua; Liu, Bingjie; Zhang, Jingmin; Li, Longyu; Wu, Jie; Jiang, Jinhua; Wang, Qingduan; Chang, Junbiao^*

来源：Journal of Medicinal Chemistry, 2016, 59(8): 3661-3670.

DOI：10.1021/acs.jmedchem.5b01807

• HEPDIRECT PRODRUGS
• DELIVERY
• PRONUCLEOTIDES
• MONOPHOSPHATE
• CHEMOTHERAPY
• MUTAGENICITY
• ACTIVATION
• MECHANISMS
• THERAPY
• DRUGS

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 (it) 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 It can release the desired 5'-monophosphate in the liver with high liver-targeting index.

• 出版日期2016-4-28
• 单位郑州大学; 河南省医药科学研究院