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首页> 外文期刊>Archiv der Pharmazie >Invesgations (correction investigations) on the influence of halide substituents on the estrogen receptor interaction of 2, 4, 5-tris(4-hydroxyphenyl)imidazoles.
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Invesgations (correction investigations) on the influence of halide substituents on the estrogen receptor interaction of 2, 4, 5-tris(4-hydroxyphenyl)imidazoles.

机译：关于卤化物取代基对2、4、5-三（4-羟苯基）咪唑的雌激素受体相互作用的影响的研究（校正研究）。

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摘要

Previously, we reported on the synthesis and estrogen receptor (ER) interaction of imidazoles, which had to be 1-alkyl-4, 5-bis(2-halo-4-hydroxyphenyl) substituted for a high relative binding affinity (RBA >1 %). This led to the assumption that a shielding of the polar heterocyclic system is a prerequisite for ER binding. In continuation of this study we synthesized 2, 4, 5-tris(4-hydroxyphenyl)imidazoles with Cl-or F-atoms in the ortho-positions of the aromatic rings and evaluated whether they mediate sufficient hydrophobicity for ER interaction. 2-(2, 6-Dichloro-3/4-hydroxyphenyl)-4, 5-bis(2-halo-4-hydroxyphenyl)imidazoles were synthesized by reaction of the respective methoxy-substituted benzil with either the 2, 6-dichloro-4-methoxy-or the 2, 6-dichloro-3-methoxybenzaldehyde in ammonium acetate solution. The required ether cleavage was performed subsequently with BBr(3). In the competition experiment with [(3)H]estradiol the imidazoles with the a C2-standing (2, 6-dichloro-4-hydroxyphenyl) ring showed an RBA >0.02 %, but did not activate the luciferase gene in estrogen receptor positive MCF-7-2a breast cancer cells stably transfected with the plasmid ERE(wtc)luc. In the test for antagonistic potency only the 2-(2, 6-dichloro-4-hydroxyphenyl)-4, 5-bis(4-hydroxyphenyl)imidazole 3 antagonized the effects of 1 nM estradiol slightly. From these data, it can be concluded that a C2-standing 2, 6-dichloro-4-hydroxyphenyl ring is not appropriate to optimize the ER interaction of 4, 5-(4-hydroxyphenyl)imidazoles.
机译：先前，我们报道了咪唑的合成和雌激素受体（ER）相互作用，咪唑必须被1-烷基-4，5-双（2-卤-4-羟基苯基）取代以较高的相对结合亲和力（RBA> 1 ％）。这导致一个假设，即极性杂环系统的屏蔽是ER结合的前提条件。在这项研究的继续中，我们合成了在芳香环邻位带有Cl-或F原子的2，4，5-三（4-羟苯基）咪唑，并评估了它们是否介导了足够的疏水性以促进ER相互作用。通过使各自的甲氧基取代的苯甲酰基与2，6-二氯中的任何一种反应合成2-（2，6-二氯-3 / 4-羟基苯基）-4，5-双（2-卤-4-羟基苯基）咪唑乙酸铵溶液中的-4-甲氧基-或2，6-二氯-3-甲氧基苯甲醛随后用BBr（3）进行所需的醚裂解。在与[（3）H]雌二醇的竞争实验中，带有C2环（2，6-二氯-4-羟基苯基）的咪唑显示RBA> 0.02％，但未激活雌激素受体阳性的萤光素酶基因用质粒ERE（wtc）luc稳定转染的MCF-7-2a乳腺癌细胞。在拮抗效力的测试中，只有2-（2,6-二氯-4-羟基苯基）-4，5-双（4-羟基苯基）咪唑3稍微拮抗了1 nM雌二醇的作用。从这些数据可以得出结论，C 2直立的2，6-二氯-4-羟基苯基环不适用于优化4，5-（4-羟基苯基）咪唑的ER相互作用。

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