Synthesis of 7alpha-substituted derivatives of 17beta-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 17beta-estradiol (E(2)) with a long side chain attached to its C-7alpha position. We explored and compared in this study various synthetic routes for preparing a number of C-7alpha-substituted derivatives of E(2), 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 E(2) as the starting material and 1-iodo-6-benzyloxyhexane as a precursor for the C-7alpha side chain, a seven-step synthetic procedure afforded 3,17beta-bis(acetoxy)-7alpha-(6-hydroxyhexanyl)-estra-1,3,5(10)-triene (one of the derivatives prepared) in an overall yield of approximately 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-17beta hydroxyls of E(2) using methoxymethyl groups; (2) hydroxylation of the C-6 position of the bismethoxymethyl ether of E(2); (3) Swern oxidation of the C-6 hydroxy to the ketone group; (4) C-7alpha alkylation of the C-6 ketone derivative of E(2); (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-7alpha-substituted derivatives of E(2) synthesized in the present study retained strong binding affinities (close to those of E(2) and ICI-182,780) for the human ERalpha and ERbeta subtypes as determined using the radioligand-receptor binding assays.
Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of South Carolina, Columbia, 29208, USA.
Xiang-Rong
XR
Jiang
J Walter
JW
Sowell
Bao Ting
BT
Zhu
D000818:Animals; D004958:Estradiol / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D004987:Ethers / Q000737:chemistry; D006586:Hexanes / Q000737:chemistry; D006801:Humans; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D013058:Mass Spectrometry / Q000379:methods; D015394:Molecular Structure; D011485:Protein Binding; D011960:Receptors, Estrogen / Q000737:chemistry; D011994:Recombinant Proteins / Q000737:chemistry; D012680:Sensitivity and Specificity; D012710:Serum Albumin, Bovine / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C511712:1-iodo-6-benzyloxyhexane; D004987:Ethers; D006586:Hexanes; D011960:Receptors, Estrogen; D011994:Recombinant Proteins; D012710:Serum Albumin, Bovine; D004958:Estradiol