In vitro inhibition of estrogen sulfoconjugation by some 2- and 4-substituted estra-1,3,5(10)-trien-17 beta-ols1a

Hormone-responsive rat and human mammary tumor, unlike normal epithelium, actively sulfoconjugates estrogens. The title compounds (9-11) were synthesized in search of specific inhibitors of estrogen sulfotransferase as a possible means of developing effective chemotherapeutic agents for treatment of hormone-dependent human mammary cancer. 4-Nitroestrone 3-triflate (7a) was converted to the corresponding estradiol derivative (8a) in 93% yield by reduction with NaBH4 under phase-transfer conditions. Catalytic reduction (10% Pd/C) of the latter gave 4-aminoestra-1,3,5(10)-trien-17 beta-ol (9a) in 77% yield. These same reactions were applied consecutively to 4-nitroestrone 3-nonaflate (7b) to give 9a in 56% overall yield. The amino steroid (9a) was converted to 4-fluoroestra-1,3,5(10)-trien-17 beta-ol (10a) via a Balz-Schiemann reaction, in 17% overall yield. Successive NaBH4 and (10% Pd/C) catalytic reductions of 4-fluoroestrone 3-O-(1-phenyl-1H-tetrazol-5-yl) ether (2b) provided a less satisfactory route to 10a. MCPBA oxidation of 9a gave 4-nitroestra-1,3,5(10)-trien-17 beta-ol (11a) in 56% yield. The same series of reactions were applied to 2-nitroestrone 3-triflate (7c) to give 2-amino- (9b), 2-fluoro- (10b), and 2-nitro- (11b) estra-1,3,5(10)-trien-17-ols in comparable yields. Substitution in the A ring results in improved inhibition of porcine endometrial sulfotransferase sulfoconjugation of estradiol relative to estra-1,3,5(10)-trien-17 beta-ol (4a). Moreover, electronegative substitution at C-4 of 4a is more effective than at C-2. In particular, the Ki (2.43 +/- 0.16 microM) of 11a is sixfold smaller than that of the unsubstituted steroid (4a).