Glucuronide and sulfate conjugates of ICI 182,780, a pure anti- estrogenic steroid. Order of addition, catalysis and substitution effects in glucuronidation
The 3-sulfate 4 and 3- and 17-glucuronide conjugates 5 and 6 of the pure anti-estrogenic steroid ICI 182,780 1, which is expected to be an effective agent for the treatment of breast cancer, have been prepared. The synthesis of 6 could only be satisfactorily achieved using an inverse addition technique, not previously employed in the glucuronic acid series: the value of this technique for some other aglycones is discussed.
Ferguson, John R.,Harding, John R.,Lumbard, Keith W.,Scheinmann, Feodor,Stachulski, Andrew V.
Putative metabolites of fulvestrant, an estrogen receptor downregulator. Improved glucuronidation using trichloroacetimidates
Following regioselective protection of the estrogen receptor downregulator fulvestrant (ICI 182,780) 1 as its 17-acetate 2 or 3-benzoate 4, the 3-sulfate 5 and 3- and 17-glucuronide conjugates 8 and 12 were prepared. Satisfactory preparation of 12 required use of the tri-O-isobutyryl imidate derivative 10 in conjunction with an inverse-addition technique not previously employed in glucuronidation. The value of this method for simpler aglycones is discussed together with a study of variations in donor acyl substituent and catalyst. Another putative metabolite, the 17-ketone 19, was prepared by direct oxidation of 1.