2-(Hydroxyalkyl)estradiols:  Synthesis and Biological Evaluation

Abstract

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.

Effects of Altering the Electronics of 2-Methoxyestradiol on Cell Proliferation, on Cytotoxicity in Human Cancer Cell Cultures, and on Tubulin Polymerization

“…Estrone (28) was reacted with BEAST to provide the 17,17-difluoro analogue 29 and with methylmagnesium bromide to create 17R-methylestradiol (30, Scheme 5). The methoxymethyl-protected derivative 31, formed by reacting estrone with diisopropylethylamine and chloromethylmethyl ether, was alkylated with methylmagnesium bromide to yield 32.…”

Homologation of Estrone or Estradiol. Appending a Carbon Substituent Into the 3-hydroxyestra-1,3,5-triene Skeleton

“…The 17-ones 39 and 41 are available by hydrolysis of the 17-OH protection and oxidation [16a, 16b] or alternatively by lithiation at C-2 of the diethylene ketal protected estrone derivative [16iii,17]. Also other electrophiles may be used after transmetalation from lithium to copper, for example CuI and allyl bromide effect 2-allylation in 66% yield [18]. The original publication for this procedure was published by Pert and Ridley already in the late eighties [19].…”

Synthesis of Oxorhenium(V) Complexes Derived from 7α-Functionalized Testosterone: First Rhenium-Containing Testosterone Derivatives

“…Moreover, the access to 7α-alkyl and -(phenylalkyl) substituents is well known [9] [10] . Therefore, we focused our attention on the introduction of a 7α-alkyl side-chain into the testosterone skeleton bearing a terminal oxorhenium(V) chelate according to the mixed-ligand concept [11] [12] .…”