SYNTHESIS AND ESTROGEN-RECEPTOR BINDING OF 6,7-DIHYDRO-8-PHENYL-9-[4-[2-(DIMETHYLAMINO)ETHOXY]PHENYL]-5H-BENZOCYCLOHEPTENE, A NON-ISOMERIZABLE ANALOG OF TAMOXIFEN - X-RAY CRYSTALLOGRAPHIC STUDIES
SYNTHESIS AND ESTROGEN-RECEPTOR BINDING OF 6,7-DIHYDRO-8-PHENYL-9-[4-[2-(DIMETHYLAMINO)ETHOXY]PHENYL]-5H-BENZOCYCLOHEPTENE, A NON-ISOMERIZABLE ANALOG OF TAMOXIFEN - X-RAY CRYSTALLOGRAPHIC STUDIES
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DOI：
10.1021/jm00160a044
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发表时间：
1986-10-01
影响因子：
7.3
通讯作者：
STOESSEL, S
中科院分区：
文献类型：
--
作者：
MCCAGUE, R;KURODA, R;STOESSEL, S
本文报道了标题化合物（5）和新的含七元环的非异构化抗雌激素药的合成。在一种方法中，6，7-二氢-9-（4-甲氧基苯基）-5H-苯并环庚烯在8-位被溴化，并且溴在钯络合物催化下被苯基氯化锌置换以引入8-苯基取代基。或者，苯并环庚酮为α。用三羰基（η 6-氟苯）铬（0）苯基化，最后用适当的芳基锂试剂处理产物以引入9-芳基。细胞胞质溶胶和全细胞中雌激素受体的相对结合亲和力以及体外对MCF-7人乳腺肿瘤细胞系的生长抑制活性5与他莫昔芬（1）和相应的六元环类似物（7）相当。10和15是5和7的甲氧基衍生物，它们的X射线晶体学分析表明，5在某些方面比萘福昔定（3）或7与他莫昔芬具有更密切的结构关系。因此，在环状类似物中稠合的芳环扭转64、45、20和19 °。分别为1、10、3和15。低温NMR研究表明，5比他莫昔芬更刚性;在NMR时间尺度上，在-75 ℃，对映异构体构象之间的相互转化率低。C.
Syntheses of the title compound (5), and novel nonisomerizable antiestrogen containing a seven-membered ring, are described. In one method, 6,7-dihydro-9-(4-methoxyphenyl)-5H-benzocycloheptene was brominated at the 8-position and the bromine displaced by phenylzinc chloride with palladium complex catalysis to introduce the 8-phenyl substituent. Alternatively, benzosuberone was .alpha. phenylated with tricarbonyl (.eta.6-fluorobenzene)chromium(0) and the product treated with the appropriate aryllithium reagent to introduce the 9-aryl group last. The relative binding affinities for estrogen receptors in cell cytosol and whole cells and growth inhibitory activity against the MCF-7 human breast tumor cell line in vitro were for 5 comparable to those of tamoxifen (1) and the corresponding six-membered ring analogue (7). X-ray crystallographic analyses of 10 and 15, which are methoxy derivatives of 5 and 7, show that in some respects 5 bears a closer structural relationship to tamoxifen than does nafoxidine (3) or 7. Thus, the aromatic ring, which is fused in the cyclic analogues, was twisted 64, 45, 20, and 19.degree. out of the plane of the double bond for 1, 10, 3, and 15, respectively. Low-temperature NMR studies indicate that 5 is more rigid than tamoxifen; interconversion between enantiomeric conformers is low on the NMR time scale at -75.degree. C.