Jordan V C, Koch R, Langan S, McCague R
Department of Human Oncology, University of Wisconsin Clinical Cancer Center, Madison 53792.
Endocrinology. 1988 Apr;122(4):1449-54. doi: 10.1210/endo-122-4-1449.
The estrogenic and antiestrogenic actions of the geometric isomers of tamoxifen and 4-hydroxytamoxifen were determined in a PRL synthesis assay using primary cultures of dispersed immature rat pituitary gland cells. 4-Hydroxytamoxifen was 100 times more potent as an antiestrogen than tamoxifen. The cis isomer of tamoxifen was a weak estrogen, but the cis isomer of 4-hydroxytamoxifen was converted to the trans isomer during the 6-day assay. This made an accurate determination of the properties of cis-(E)4-hydroxytamoxifen impossible. A series of fixed ring derivatives of the compounds were evaluated in the PRL synthesis assay in vitro to determine their estrogenic and antiestrogenic activities. The fixed ring derivatives of tamoxifen, cis-tamoxifen and trans-(Z)4-hydroxytamoxifen all had properties that were the same as those of the original triphenylethylenes. The fixed ring derivative of the cis-(E) isomer of 4-hydroxytamoxifen was a weak competitive antagonist of estrogen action with only very slight estrogenic properties. This contrasted with the other cis isomers of triphenylethylenes. We propose that the hydroxyl group on the molecule may orient the ligand at the binding site of the estrogen receptor to place the alkylaminoethoxy side-chain in a position to produce antiestrogen action.
利用分散的未成熟大鼠垂体腺细胞原代培养物，在泌乳素（PRL）合成试验中测定了他莫昔芬和4-羟基他莫昔芬几何异构体的雌激素和抗雌激素作用。4-羟基他莫昔芬作为抗雌激素的效力比他莫昔芬强100倍。他莫昔芬的顺式异构体是一种弱雌激素，但在为期6天的试验中，4-羟基他莫昔芬的顺式异构体转化为反式异构体。这使得无法准确测定顺式-（E）4-羟基他莫昔芬的性质。在体外PRL合成试验中评估了该化合物的一系列固定环衍生物，以确定它们的雌激素和抗雌激素活性。他莫昔芬、顺式他莫昔芬和反式-（Z）4-羟基他莫昔芬的固定环衍生物都具有与原始三苯乙烯相同的性质。4-羟基他莫昔芬顺式-（E）异构体的固定环衍生物是雌激素作用的弱竞争性拮抗剂，仅具有非常轻微的雌激素性质。这与三苯乙烯的其他顺式异构体形成对比。我们提出，分子上的羟基可能使配体在雌激素受体的结合位点定向，从而使烷基氨基乙氧基侧链处于产生抗雌激素作用的位置。
