Prolonged exposure to estrogens as hormone replacement therapy agents to relieve menopausal symptoms
is linked to an increased risk of breast and other types of human cancers. Previous studies showed the carcinogenic
effect of estrogens occurred through formation of carcinogenic/tumor initiating quinone metabolites.
Hence, it was found that occupying both ortho-positions by substituents on the A-ring effectively prevent the quinone
formation. Hence, a new substituted phenolic series of A-CD estrogen family, where the five-membered Dring
is substituted with a six-membered one, was designed and synthesized. Desired compounds were prepared by
stereospecific reduction of Wieland-Miescher ketone followed by coupling with lithiated protected phenols. Dehydration
of corresponding alcohols afforded the alkene intermediates. Final hydrogenation removed the protecting
group and selectively reduced the double bond to give the desired 9-(S)-isomer.
Keywords: 17β-Estradiol, A-CD analogs, non-quinone forming ligands, stereoselectivity, wieland-miescher ketone, carcinogenicity.
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