title: Synthesis and characterization of a novel liver-targeted prodrug of cytosine-1-beta-D-arabinofuranoside monophosphate for the treatment of hepatocellular carcinoma.
abstract: 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 tumor and high conversion in other tissues. These characteristics lead to poor efficacy, high toxicity, and a drug class associated with an unacceptable therapeutic index. Cyclic 1-aryl-1,3-propanyl phosphate prodrugs selectively release the monophosphate of a nucleoside (NMP) into CYP3A4-expressing cells, such as hepatocytes, while leaving the prodrug intact in plasma and extrahepatic tissues. This prodrug strategy was applied to the monophosphate of the well-known cytotoxic nucleoside cytosine-1-beta-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 the plasma and >12-fold higher araCTP levels in the liver than in the bone marrow, representing a >120-fold and >28-fold improvement, respectively, over araC administration.
authors.affiliation: Departments of Medicinal Chemistry and Biosciences, Metabasis Therapeutics, Inc., 11119 North Torrey Pines Road, La Jolla, CA 92037, USA. boyer@mbasis.com
authors.forename: Serge H
authors.initials: SH
authors.lastname: Boyer
authors.forename: Zhili
authors.initials: Z
authors.lastname: Sun
authors.forename: Hongjian
authors.initials: H
authors.lastname: Jiang
authors.forename: Julie
authors.initials: J
authors.lastname: Esterbrook
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Gómez-Galeno
authors.forename: William
authors.initials: W
authors.lastname: Craigo
authors.forename: K Raja
authors.initials: KR
authors.lastname: Reddy
authors.forename: Bheemarao G
authors.initials: BG
authors.lastname: Ugarkar
authors.forename: Deidre A
authors.initials: DA
authors.lastname: MacKenna
authors.forename: Mark D
authors.initials: MD
authors.lastname: Erion
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D001085:Arabinofuranosylcytosine Triphosphate / Q000097:blood; D001088:Arabinonucleotides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D002851:Chromatography, High Pressure Liquid; D003568:Cytidine Monophosphate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects*; D008113:Liver Neoplasms / Q000188:drug therapy; D008297:Male; D051379:Mice; D011355:Prodrugs / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D001088:Arabinonucleotides; D011355:Prodrugs; D001085:Arabinofuranosylcytosine Triphosphate; C024888:1-beta-D-arabinofuranosylcytosine 5'-monophosphate; D003568:Cytidine Monophosphate