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

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

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32 Scopus citations

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).

Original languageEnglish (US)
Pages (from-to)9334-9344
Number of pages11
JournalJournal of medicinal chemistry
Volume58
Issue number23
DOIs
StatePublished - Dec 10 2015

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Publisher Copyright:
© 2015 American Chemical Society.

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