Synthesis of 7α-substituted derivatives of 17β-estradiol

Estrogen receptor (ER) pure antagonists such as ICI-182,780 (fulvestrant) are effective alternatives to tamoxifen (an ER antagonist/weak partial agonist) in the treatment of postmenopausal, receptor-positive human breast cancers. Structurally, these pure antagonists contain the basic core structure of 17β-estradiol (E2) with a long side chain attached to its C-7α position. We explored and compared in this study various synthetic routes for preparing a number of C-7α-substituted derivatives of E2, which are highly useful for the design and synthesis of high-affinity ER antagonists, ER-based imaging ligands, and other ER-based multi-functional agents. Using E2 as the starting material and 1-iodo-6-benzyloxyhexane as a precursor for the C-7α side chain, a seven-step synthetic procedure afforded 3,17β-bis(acetoxy)-7α-(6-hydroxyhexanyl)-estra-1,3,5(10)-triene (one of the derivatives prepared) in an overall yield of ∼45% as compared to other known procedures that afforded substantially lower overall yield (8–27%). The synthetic steps for this representative compound include: (1) protection of the C-3 and C-17β hydroxyls of E2 using methoxymethyl groups; (2) hydroxylation of the C-6 position of the bismethoxymethyl ether of E2; (3) Swern oxidation of the C-6 hydroxy to the ketone group; (4) C-7α alkylation of the C-6 ketone derivative of E2; (5) deprotection of the two methoxymethyl groups; (6) reprotection of the C-3 and C-6 free hydroxyls with acetyl groups; (7) removal of the C-6 ketone and the benzyl group on the side chain by catalytic hydrogenation in acetic acid. As predicted, two of the representative C-7α-substituted derivatives of E2 synthesized in the present study retained strong binding affinities (close to those of E2 and ICI-182,780) for the human ERα and ERβ subtypes as determined using the radioligand–receptor binding assays.