Synthesis, conformational considerations, and estrogen receptor binding of diastereoisomers and enantiomers of 1-[4-[2-(dimethylamino)ethoxy]phenyl]-1,2-diphenylbutane (dihydrotamoxifen).

As part of a study into nonisomerizable antiestrogens, the diastereoisomeric dihydrotamoxifens 7 and 8 were prepared by catalytic transfer hydrogenation of (Z)- and (E)-tamoxifen and were shown by NMR spectrometry to exist in preferred conformations with hydrogen atoms in an antiperiplanar relationship. The corresponding 4-hydroxy derivatives 9 and 10 were prepared from hydrogenated precursors of (Z)- and (E)-4-hydroxytamoxifen. The relative binding affinities (RBA) of the compounds to estrogen receptors are consistent with the assigned conformations and parallel reported data on derivatives of the nonsteroidal estrogen hexestrol. The growth-inhibitory activity against the MCF-7 human breast cancer cell line in vitro was for 10 comparable to that of 4-hydroxytamoxifen, although increasing the concentration from 10(-8) to 10(-6) M did not significantly improve the growth inhibition. The derivative 9 analogous to (E)-4-hydroxytamoxifen antagonized the growth-stimulating effect of added estradiol and is therefore also an antiestrogen but at low concentration (10(-8) M) in the absence of estradiol, MCF-7 cell growth was stimulated, indicating an estrogenic influence. The enantiomers of the dihydrotamoxifen 8 were individually prepared from the resolved enantiomers of 2-phenylbutanoic acid, the key reaction step being a lithium-ammonia reduction of the 1-(4-methoxyphenyl)-1,2-diphenyl-1-butanol to generate the triphenylbutane. The enantiomers of 8 gave identical RBA values in cytosol.