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).
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / drug therapy*
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Adenocarcinoma / pathology
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / therapeutic use*
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Cell Line, Tumor
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Colon / drug effects
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Colon / pathology
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Colonic Neoplasms / drug therapy*
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Colonic Neoplasms / pathology
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Diterpenes
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Drug Stability
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Epoxy Compounds
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Female
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HT29 Cells
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Humans
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Mice
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Mice, Nude
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Organophosphates / chemical synthesis
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Organophosphates / chemistry
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Organophosphates / therapeutic use*
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Ovarian Neoplasms / drug therapy*
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Ovarian Neoplasms / pathology
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Ovary / drug effects
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Ovary / pathology
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Phenanthrenes / chemical synthesis
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Phenanthrenes / chemistry
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Phenanthrenes / therapeutic use*
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Prodrugs / chemical synthesis
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Prodrugs / chemistry
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Prodrugs / therapeutic use*
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Solubility
Substances
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Antineoplastic Agents
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Diterpenes
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Epoxy Compounds
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Organophosphates
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Phenanthrenes
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Prodrugs
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14-O-phosphonooxymethyltriptolide disodium salt