Napolitano E, Fiaschi R, Herman L W, Hanson R N
Department of Pharmaceutical Sciences, Bouve College of Pharmacy and Health Sciences, Northeastern University, Boston, Massachusetts 02115, USA.
Steroids. 1996 Jun;61(6):384-9. doi: 10.1016/0039-128x(96)00045-1.
Previous studies from our laboratory using 17 alpha-E- and 17 alpha-Z-halovinyl estradiols demonstrated a marked enhancement of receptor binding by the Z-isomers. This suggested tolerance at the 17 alpha-position was not previously observed by investigations using 16 alpha and 17 alpha-substituted estradiols. Because of the synthetic access provided by vinyl tin chemistry, we prepared the 17 alpha-E and Z-phenylthiovinyl and phenylselenovinyl estradiols and compared their binding characteristics to those of the previously reported 16 alpha/17 alpha-phenylseleno and methylseleno estradiols. The results, in addition to demonstrating a facile preparation of the target compounds, indicated that significant receptor affinity was retained by these compounds (relative binding affinity = 24.5-117). The highest affinity was demonstrated by the 17 alpha-Z-phenylthiovinyl estradiol 5a, which, by molecular modeling, exhibited a significantly different molecular conformation from the corresponding 17 alpha-E-phenylthiovinyl isomer or the 17 alpha-phenyl-thioethynyl analog. The current series possessed better binding characteristics than the phenylseleno and methylseleno estradiols but somewhat poorer binding than the 17 alpha-E/Z-halovinyl series. The observations suggest that some steric limitations exist in a portion of the 17 alpha-region, and that the region is better accessed by compounds possessing Z-vinyl stereochemistry.
我们实验室之前使用17α-E-和17α-Z-卤乙烯基雌二醇的研究表明，Z-异构体的受体结合能力显著增强。这表明，以前使用16α和17α-取代雌二醇的研究未观察到17α位的耐受性。由于乙烯基锡化学提供了合成途径，我们制备了17α-E-和Z-苯硫基乙烯基及苯硒基乙烯基雌二醇，并将它们的结合特性与先前报道的16α/17α-苯硒基和甲基硒基雌二醇的结合特性进行了比较。结果除了表明目标化合物易于制备外，还表明这些化合物保留了显著的受体亲和力（相对结合亲和力 = 24.5 - 117）。17α-Z-苯硫基乙烯基雌二醇5a表现出最高的亲和力，通过分子模拟，它与相应的17α-E-苯硫基乙烯基异构体或17α-苯硫乙炔基类似物具有显著不同的分子构象。当前系列的结合特性优于苯硒基和甲基硒基雌二醇，但比17α-E/Z-卤乙烯基系列略差。这些观察结果表明，17α区域的一部分存在一些空间限制，并且具有Z-乙烯基立体化学的化合物更容易进入该区域。
