Phosphonooxymethyl Prodrug of Triptolide: Synthesis, Physicochemical Characterization, and Efficacy in Human Colon Adenocarcinoma and Ovarian Cancer Xenografts

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• 作者：Satish Patil ; Lev G. Lis ; Robert J. Schumacher ; Beverly J. Norris ; Monique L. Morgan ; Rebecca A. D. Cuellar ; Bruce R. Blazar ; Raj Suryanarayanan ; Vadim J. Gurvich ; Gunda I. Georg
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：December 10, 2015
• 年：2015
• 卷：58
• 期：23
• 页码：9334-9344
• 全文大小：566K
• ISSN：1520-4804

文摘

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 渭g/mL). The estimated shelf life (t₉₀) for hydrolysis of the prodrug at 4 掳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).