title: Discovery of an Orally Active and Liver-Targeted Prodrug of 5-Fluoro-2'-Deoxyuridine for the Treatment of Hepatocellular Carcinoma.
abstract: 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.
authors.affiliation: Henan Academy of Medical and Pharmaceutical Sciences, Zhengzhou University , Zhengzhou 450052, People's Republic of China.
authors.forename: Youmei
authors.initials: Y
authors.lastname: Peng
authors.forename: Wenquan
authors.initials: W
authors.lastname: Yu
authors.forename: Ertong
authors.initials: E
authors.lastname: Li
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Kang
authors.forename: Yafeng
authors.initials: Y
authors.lastname: Wang
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Yang
authors.forename: Bingjie
authors.initials: B
authors.lastname: Liu
authors.forename: Jingmin
authors.initials: J
authors.lastname: Zhang
authors.forename: Longyu
authors.initials: L
authors.lastname: Li
authors.forename: Jie
authors.initials: J
authors.lastname: Wu
authors.affiliation: Henan Academy of Medical and Pharmaceutical Sciences, Zhengzhou University , Zhengzhou 450052, People's Republic of China.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Henan Academy of Medical and Pharmaceutical Sciences, Zhengzhou University , Zhengzhou 450052, People's Republic of China.
authors.forename: Qingduan
authors.initials: Q
authors.lastname: Wang
authors.forename: Junbiao
authors.initials: J
authors.lastname: Chang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D019540:Area Under Curve; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D003857:Deoxyuridine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D055808:Drug Discovery; D008099:Liver / Q000187:drug effects*; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy*; D051379:Mice; D011355:Prodrugs / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: C576827:5-fluoro-2'-deoxyuridine; D000970:Antineoplastic Agents; D011355:Prodrugs; D003857:Deoxyuridine