Synthesis and in vivo antitumor evaluation of 2-methoxyestradiol 3-phosphate, 17-phosphate, and 3,17-diphosphate.
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-methoxyestradiol 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.
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, The Purdue Cancer Center, Purdue University, West Lafayette, IN 47907, USA.
Allison B
AB
Edsall
Gregory E
GE
Agoston
Anthony M
AM
Treston
Stacy M
SM
Plum
Robert H
RH
McClanahan
Tian-Sheng
TS
Lu
Wei
W
Song
Mark
M
Cushman
D000077584:2-Methoxyestradiol; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy / Q000556:secondary; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D004958:Estradiol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010755:Organophosphates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
C527729:2-methoxyestradiol 17-phosphate; C527730:2-methoxyestradiol 3,17-diphosphate; C527728:2-methoxyestradiol 3-phosphate; D000970:Antineoplastic Agents; D010755:Organophosphates; D011355:Prodrugs; D004958:Estradiol; D000077584:2-Methoxyestradiol