1. Phosphonooxymethyl Prodrug of Triptolide: Synthesis, Physicochemical Characterization, and Efficacy in Human Colon Adenocarcinoma and Ovarian Cancer Xenografts
- Author
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Beverly Norris, Rebecca A. D. Cuellar, Satish Patil, Robert J. Schumacher, Bruce R. Blazar, Lev G Lis, Raj Suryanarayanan, Vadim J. Gurvich, Monique Morgan, and Gunda I. Georg
- Subjects
Colon ,Mice, Nude ,Antineoplastic Agents ,Ovary ,Adenocarcinoma ,Pharmacology ,Article ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Drug Stability ,Cell Line, Tumor ,Drug Discovery ,medicine ,Animals ,Humans ,Prodrugs ,Solubility ,030304 developmental biology ,Ovarian Neoplasms ,0303 health sciences ,Natural product ,Chemistry ,Phenanthrenes ,Prodrug ,Triptolide ,medicine.disease ,Organophosphates ,3. Good health ,medicine.anatomical_structure ,Cell culture ,030220 oncology & carcinogenesis ,Colonic Neoplasms ,Epoxy Compounds ,Molecular Medicine ,Female ,Diterpenes ,Ovarian cancer ,HT29 Cells - 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).
- Published
- 2015