title: Phosphonooxymethyl Prodrug of Triptolide: Synthesis, Physicochemical Characterization, and Efficacy in Human Colon Adenocarcinoma and Ovarian Cancer Xenografts.
abstract: A disodium phosphonooxymethyl prodrug of the antitumor agent triptolide was prepared from the natural product in three steps (39% yield) and displayed excellent aqueous solubility at pH 7.4 (61 mg/mL) compared to the natural product (17 μg/mL). The estimated shelf life (t90) for hydrolysis of the prodrug at 4 °C and pH 7.4 was found to be two years. In a mouse model of human colon adenocarcinoma (HT-29), the prodrug administered intraperitoneally was effective in reducing or eliminating xenograft tumors at dose levels as low as 0.3 mg/kg when given daily and at 0.9 mg/kg when given less frequently. When given via intraperitoneal and oral routes at daily doses of 0.6 and 0.9 mg/kg, the prodrug was also effective and well tolerated in a mouse model of human ovarian cancer (A2780).
authors.affiliation: Department of Medicinal Chemistry and Institute for Therapeutics Discovery and Development, College of Pharmacy, University of Minnesota , 717 Delaware Street SE, Minneapolis, Minnesota 55414, United States.
authors.forename: Satish
authors.initials: S
authors.lastname: Patil
authors.affiliation: Department of Medicinal Chemistry and Institute for Therapeutics Discovery and Development, College of Pharmacy, University of Minnesota , 717 Delaware Street SE, Minneapolis, Minnesota 55414, United States.
authors.forename: Lev G
authors.initials: LG
authors.lastname: Lis
authors.affiliation: Center for Translational Medicine, Academic Health Center, University of Minnesota , 420 Delaware Street SE, Minneapolis, Minnesota 55455, United States.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schumacher
authors.affiliation: Center for Translational Medicine, Academic Health Center, University of Minnesota , 420 Delaware Street SE, Minneapolis, Minnesota 55455, United States.
authors.forename: Beverly J
authors.initials: BJ
authors.lastname: Norris
authors.affiliation: Center for Translational Medicine, Academic Health Center, University of Minnesota , 420 Delaware Street SE, Minneapolis, Minnesota 55455, United States.
authors.forename: Monique L
authors.initials: ML
authors.lastname: Morgan
authors.affiliation: Department of Medicinal Chemistry and Institute for Therapeutics Discovery and Development, College of Pharmacy, University of Minnesota , 717 Delaware Street SE, Minneapolis, Minnesota 55414, United States.
authors.forename: Rebecca A D
authors.initials: RA
authors.lastname: Cuellar
authors.affiliation: Center for Translational Medicine, Academic Health Center, University of Minnesota , 420 Delaware Street SE, Minneapolis, Minnesota 55455, United States.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Minnesota , 308 Harvard Street SE, Minneapolis, Minnesota 55455, United States.
authors.forename: Raj
authors.initials: R
authors.lastname: Suryanarayanan
authors.affiliation: Department of Medicinal Chemistry and Institute for Therapeutics Discovery and Development, College of Pharmacy, University of Minnesota , 717 Delaware Street SE, Minneapolis, Minnesota 55414, United States.
authors.forename: Vadim J
authors.initials: VJ
authors.lastname: Gurvich
authors.affiliation: Department of Medicinal Chemistry and Institute for Therapeutics Discovery and Development, College of Pharmacy, University of Minnesota , 717 Delaware Street SE, Minneapolis, Minnesota 55414, United States.
authors.forename: Gunda I
authors.initials: GI
authors.lastname: Georg
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003106:Colon / Q000187:drug effects / Q000473:pathology; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004224:Diterpenes; D004355:Drug Stability; D004852:Epoxy Compounds; D005260:Female; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010755:Organophosphates / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010053:Ovary / Q000187:drug effects / Q000473:pathology; D010616:Phenanthrenes / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D012995:Solubility
chemical_list: D000970:Antineoplastic Agents; D004224:Diterpenes; D004852:Epoxy Compounds; D010755:Organophosphates; D010616:Phenanthrenes; D011355:Prodrugs; C579022:14-O-phosphonooxymethyltriptolide disodium salt