McCague R, Leclercq G, Jordan V C
Drug Development Section, Institute of Cancer Research, Sutton, Surrey, U.K.
J Med Chem. 1988 Jul;31(7):1285-90. doi: 10.1021/jm00402a005.
Substituted 8,9-diphenyl-6,7-dihydro-5H-benzocycloheptenes 6-8, which are ring-fused analogues of (Z)-trans-4-hydroxytamoxifen, (E)-cis-tamoxifen, and (E)-cis-4-hydroxytamoxifen, were synthesized from 7-methoxy-1-benzosuberone. The hydroxy compounds 6 and 8 were individually prepared via a common synthetic intermediate from which either the perfluoro-p-tolyl or the methyl ether functions could be cleaved specifically. Compounds were assayed for binding affinity to estrogen receptors in cytosol and in MCF-7 whole cells and for growth inhibition of MCF-7 cells in vitro and rat uteri in vivo. The endocrinological properties of the cyclic analogues 5-7 paralleled those of the corresponding derivatives of tamoxifen although in the MCF-7 assay 6 was slightly less effective than 4-hydroxytamoxifen at 10(-6) and 10(-7) M. The compound 8 analogues to cis-4-hydroxytamoxifen antagonized the growth stimulation by estradiol of MCF-7 cell or rat uterus growth, and it is therefore an antiestrogen, but its potency was somewhat less, both as an antiestrogen and an estrogen, than reported for cis-4-hydroxytamoxifen attributable to modification of the biochemical properties of the latter by isomerization to the more potent trans isomer. Curiously, in the absence of estradiol, compound 8 stimulated MCF-7 cell growth at low concentration (10(-8) M) but inhibited growth at higher concentration. In contrast, compound 7, which lacked the hydroxy function, was a full estrogen in the rat uterine growth assay. These compounds should be ideal for further structure-activity studies of triarylethylene-based antiestrogens without complications caused by isomerization.
取代的8,9 - 二苯基 - 6,7 - 二氢 - 5H - 苯并环庚烯6 - 8是(Z)-反式 - 4 - 羟基他莫昔芬、(E)-顺式 - 他莫昔芬和(E)-顺式 - 4 - 羟基他莫昔芬的稠环类似物，由7 - 甲氧基 - 1 - 苯并环庚酮合成。羟基化合物6和8分别通过一种常见的合成中间体制备，从中可以特异性地裂解全氟对甲苯基或甲基醚官能团。对化合物进行了测定，以检测其对胞质溶胶和MCF - 7全细胞中雌激素受体的结合亲和力，以及对MCF - 7细胞的体外生长抑制和对大鼠子宫的体内生长抑制。环状类似物5 - 7的内分泌特性与他莫昔芬相应衍生物的特性相似，尽管在MCF - 7试验中，在10(-6)和10(-7) M浓度下，6的效果略低于4 - 羟基他莫昔芬。与顺式 - 4 - 羟基他莫昔芬类似的化合物8拮抗了雌二醇对MCF - 7细胞生长或大鼠子宫生长的刺激作用，因此它是一种抗雌激素，但作为抗雌激素和雌激素，其效力均略低于报道的顺式 - 4 - 羟基他莫昔芬，这归因于后者通过异构化为更有效的反式异构体而改变了生化性质。奇怪的是，在没有雌二醇的情况下，化合物8在低浓度(10(-8) M)时刺激MCF - 7细胞生长，但在高浓度时抑制生长。相比之下，缺乏羟基官能团的化合物7在大鼠子宫生长试验中是一种完全的雌激素。这些化合物对于基于三芳基乙烯的抗雌激素的进一步构效关系研究应该是理想的，不会因异构化而产生并发症。
