Napolitano E, Fiaschi R, Hanson R N
College of Pharmacy & Allied Health Professions, Section of Medicinal Chemistry, Northeastern University, Boston, Massachusetts 02115.
J Med Chem. 1991 Sep;34(9):2754-9. doi: 10.1021/jm00113a012.
As part our program to probe the molecular requirement for estrogen-receptor binding we undertook the synthesis and evaluation of the 17 alpha,E and 17 alpha,Z halovinyl estradiols. By use of an improved variation of the existing synthetic strategy, the targeted compounds were prepared stereospecifically and in 92-98% yields from the corresponding 17 alpha,E or 17 alpha,Z [(tri-n-butylstannyl)vinyl]estradiol 3-acetates. The novel estradiol derivatives were evaluated for their relative binding affinity (RBA) for the estrogen receptor with use of a rat uterine preparation. The results demonstrated a marked difference between the E and Z isomers and among the halogen employed. The Z isomers possessed significantly higher RBA values and the larger halogens (I, Br) were more effective than the smaller Cl substituent. These results modify the previous interpretations of estrogen-receptor binding for steroidal ligands. As a result, our design of (radio)halogenated ligands will incorporate this concern for Z vs E stereochemistry.
作为我们探索雌激素受体结合分子要求计划的一部分，我们开展了17α,E和17α,Z卤代乙烯基雌二醇的合成与评估。通过对现有合成策略进行改进，从相应的17α,E或17α,Z [(三正丁基锡基)乙烯基]雌二醇3 - 乙酸酯立体定向制备了目标化合物，产率为92 - 98%。使用大鼠子宫制剂评估了这些新型雌二醇衍生物对雌激素受体的相对结合亲和力（RBA）。结果表明E异构体和Z异构体之间以及所使用的卤素之间存在显著差异。Z异构体具有明显更高的RBA值，并且较大的卤素（I、Br）比较小的Cl取代基更有效。这些结果改变了先前对甾体配体雌激素受体结合的解释。因此，我们（放射性）卤化配体的设计将纳入对Z与E立体化学的考虑。
