Synthesis and in Vivo Antitumor Evaluation of 2-Methoxyestradiol 3-Phosphate,17-Phosphate,and 3,17-Diphosphate

摘要

A prodrug strategy was investigated to address the problem of limited aqueous solubility and the resulting limited bioavailability of the antitumor agent 2-methoxyestradiol.The 3-phosphate,17-phosphate,and 3,17-diphosphate of 2-methoxyestradiol were synthesized.2-Methoxyestradiol 3-phosphate was metabolized more efficiently to the parent compound in vivo than 2-methoxyestradiol 17-phosphate,and it was also more cytotoxic in cancer cell cultures than either the 17-phosphate or the 3,17-diphosphate.These results agree with the in vivo anticancer activity of 2-mefhoxyestradiol 3-phosphate in a mouse Lewis lung carcinoma experimental metastasis model as opposed to the 17-phosphate and 3,17-diphosphate,both of which were inactive.The in vivo antitumor activity of 2-methoxyestradiol 3-phosphate at a dose of 200 mg/kg per day was comparable to that of a maximally tolerated dose of cyclophosphamide.