Jonson S D, d'Avignon D A, Katzenellenbogen J A, Welch M J
Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, Missouri 63110, USA.
Steroids. 1998 Sep;63(9):470-8. doi: 10.1016/s0039-128x(98)00051-8.
The usual chemistry of methyl hypofluorite provides a previously unexplored route for functionalizing the 16-position of estradiol. Three isomers of 16-methoxyestradiol were prepared via two synthetic routes, each using methyl hypofluorite. The estrogen receptor binding affinity of these compounds was determined to evaluate their potential as positron emission tomographic (PET) imaging agents targeting estrogen receptor-positive breast cancer. Radiolabeled methyl hypofluorite ([11C]CH3OF) would allow the rapid preparation of novel carbon-11 PET imaging agents. The 17-trimethylsilyl enol ethers of 3-benzyloxy and 3-trifloxyestrone were prepared as substrates to react with methyl hypofluorite. Conditions for the reaction of methyl hypofluorite with simple substrates were optimized to provide reasonable reaction yields with the steroidal substrates. Following introduction of the methoxy substituent at the 16-position, reduction and deprotection conditions were manipulated to yield the various methoxyestradiol isomers. Two-dimensional NMR techniques (HMQC and HMQC-TOCSY) were instrumental in the characterization of the methoxyestradiol isomers. NOESY experiments confirmed the stereochemistry of the 16- and 17-positions. 16 alpha-Methoxyestradiol-17 beta and 16 beta-methoxyestradiol-17 beta each with the preferred beta orientation for the 17-alcohol, were determined to have relative binding affinities of 1.5% and 2.3%, respectively. The stereoisomer with the unfavored alpha orientation at the 17-position, 16 alpha-methoxyestradiol-17 alpha, exhibited only a 0.5% relative binding affinity for the estrogen receptor. The biological evaluation of these compounds was not pursued further because of their low binding affinities.
次氟酸甲酯的常规化学性质为雌二醇16位官能团化提供了一条前所未有的途径。通过两条合成路线制备了三种16 - 甲氧基雌二醇异构体，每条路线均使用了次氟酸甲酯。测定了这些化合物的雌激素受体结合亲和力，以评估它们作为正电子发射断层扫描（PET）成像剂靶向雌激素受体阳性乳腺癌的潜力。放射性标记的次氟酸甲酯（[¹¹C]CH₃OF）将有助于快速制备新型碳 - 11 PET成像剂。制备了3 - 苄氧基雌酮和3 - 三氟氧基雌酮的17 - 三甲基硅基烯醇醚作为与次氟酸甲酯反应的底物。优化了次氟酸甲酯与简单底物的反应条件，以在甾体底物上获得合理的反应产率。在16位引入甲氧基取代基后，对还原和脱保护条件进行调控以得到各种甲氧基雌二醇异构体。二维核磁共振技术（HMQC和HMQC - TOCSY）有助于甲氧基雌二醇异构体的表征。NOESY实验确定了16位和17位的立体化学结构。16α - 甲氧基雌二醇 - 17β和16β - 甲氧基雌二醇 - 17β，其17 - 醇均具有优选的β构型，测定其相对结合亲和力分别为1.5%和2.3%。在17位具有不利α构型的立体异构体16α - 甲氧基雌二醇 - 17α，对雌激素受体的相对结合亲和力仅为0.5%。由于这些化合物的结合亲和力较低，未进一步进行生物学评估。
