Discovery of an Orally Active and Liver-Targeted Prodrug of 5-Fluoro-2′-Deoxyuridine for the Treatment of Hepatocellular Carcinoma
| Autor: | Youmei Peng, Junbiao Chang, Yafeng Wang, Qingduan Wang, Jinfeng Kang, Jinhua Jiang, Ertong Li, Bingjie Liu, Longyu Li, Wenquan Yu, Jie Wu, Qinghua Yang, Jingmin Zhang |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Carcinoma Hepatocellular Administration Oral Antineoplastic Agents Pharmacology Rats Sprague-Dawley Mice 03 medical and health sciences chemistry.chemical_compound Liver Neoplasms Experimental 0302 clinical medicine Oral administration Drug Discovery medicine Animals Prodrugs Tissue Distribution Phosphoramidate Prodrug medicine.disease Deoxyuridine Rats Bioavailability 030104 developmental biology Orally active Liver chemistry Area Under Curve 030220 oncology & carcinogenesis Hepatocellular carcinoma Molecular Medicine Lead compound |
| Zdroj: | Journal of Medicinal Chemistry. 59:3661-3670 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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