Synthesis and Characterization of a Novel Liver-Targeted Prodrug of Cytosine-1--D-arabinofuran
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- 作者：Serge H. Boyer ; Zhili Sun ; Hongjian Jiang ; Julie Esterbrook ; Jorge E. Gó ; mez-Galeno ; William Craigo ; K. Raja Reddy ; Bheemarao G. Ugarkar ; Deidre A. MacKenna ; Mark D. Erion
- 刊名：Journal of Medicinal Chemistry
- 出版年：2006
- 出版时间：December 28, 2006
- 年：2006
- 卷：49
- 期：26
- 页码：7711 - 7720
- 全文大小：167K
- 年卷期：v.49,no.26(December 28, 2006)
- ISSN：1520-4804
文摘
Cytotoxic nucleosides have proven to be ineffective for the treatment of hepatocellular carcinoma (HCC)due, in part, to their inadequate conversion to their active nucleoside triphosphates (NTP) in the liver tumorand high conversion in other tissues. These characteristics lead to poor efficacy, high toxicity, and a drugclass associated with an unacceptable therapeutic index. Cyclic 1-aryl-1,3-propanyl phosphate prodrugsselectively release the monophosphate of a nucleoside (NMP) into CYP3A4-expressing cells, such ashepatocytes, while leaving the prodrug intact in plasma and extrahepatic tissues. This prodrug strategy wasapplied to the monophosphate of the well-known cytotoxic nucleoside cytosine-1-
-D-arabinofuranoside(cytarabine, araC). Compound 19S (MB07133), in mice, achieves good liver targeting compared to araC,generating >19-fold higher cytarabine triphosphate (araCTP) levels in the liver than levels of araC in theplasma and >12-fold higher araCTP levels in the liver than in the bone marrow, representing a >120-foldand >28-fold improvement, respectively, over araC administration.
-D-arabinofuranoside(cytarabine, araC). Compound 19S (MB07133), in mice, achieves good liver targeting compared to araC,generating >19-fold higher cytarabine triphosphate (araCTP) levels in the liver than levels of araC in theplasma and >12-fold higher araCTP levels in the liver than in the bone marrow, representing a >120-foldand >28-fold improvement, respectively, over araC administration.