Lovely C J, Gilbert N E, Liberto M M, Sharp D W, Lin Y C, Brueggemeier R W
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Ohio State University, Columbus 43210, USA.
J Med Chem. 1996 Apr 26;39(9):1917-23. doi: 10.1021/jm9508245.
Synthetic estrogens possessing hydroxyalkyl side chains at the C-2 position of the A-ring were designed in order to further elucidate the structural and electronic requirements of the estrogen receptor to A-ring modifications. Furthermore, these compounds were envisaged as being stable analogs of the estradiol metabolite 2-hydroxyestradiol. The homologous series of 2-(hydroxyalkyl)estradiols 1-3 has been prepared by chain extension of 2-formylestradiol 6, which, in turn, was prepared via ortholithiation of estradiol. The substituted estradiols 1-3 were assayed for their abilities to bind to the estrogen receptor in MCF-7 cells and induce estrogen-responsive gene expression. The estradiol homologs exhibited significantly weaker affinity than estradiol for the MCF-7 cell estrogen receptor, with relative binding affinities (estradiol = 100) ranging from 1.11 for 2-(hydroxymethyl)estradiol (1) to 0.073 for 2-(hydroxypropyl)estradiol (3). The relative activities for mRNA induction of the pS2 gene by the estradiol homologs closely parallel the relative binding affinities for the estrogen receptor in MCF-7 cells. 2-(Hydroxymethyl)-estradiol exhibited similar estrogen receptor affinity and pS2 gene induction to the catechol estrogen 2-hydroxyestradiol and may prove useful in examination of the further biological effects of 2-hydroxyestrogen homologs.
设计了在A环C-2位带有羟烷基侧链的合成雌激素，以进一步阐明雌激素受体对A环修饰的结构和电子要求。此外，这些化合物被设想为雌二醇代谢物2-羟雌二醇的稳定类似物。通过2-甲酰基雌二醇6的链延长制备了2-(羟烷基)雌二醇1-3的同系物系列，而2-甲酰基雌二醇6又是通过雌二醇的邻位锂化制备的。测定了取代雌二醇1-3与MCF-7细胞中雌激素受体结合并诱导雌激素反应性基因表达的能力。雌二醇同系物对MCF-7细胞雌激素受体的亲和力明显低于雌二醇，相对结合亲和力(雌二醇=100)范围从2-(羟甲基)雌二醇(1)的1.11到2-(羟丙基)雌二醇(3)的0.073。雌二醇同系物对pS2基因mRNA诱导的相对活性与MCF-7细胞中雌激素受体的相对结合亲和力密切平行。2-(羟甲基)雌二醇对雌激素受体的亲和力和对pS2基因的诱导作用与儿茶酚雌激素2-羟雌二醇相似，可能有助于研究2-羟雌激素同系物的进一步生物学效应。
