Diethylstilbestrol metabolites and analogs. Biochemical probes for differential stimulation of uterine estrogen responses.

Korach, Kenneth S.; Fox-Davies, Christine; Quarmby, Valerie; Swaisgood, Mark

doi:10.1016/s0021-9258(17)36270-1

Cited by 35 publications

(7 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Fetal and neonatal DES exposure elicits distinct and permanent alterations in the female reproductive tract [44]. DES has a high binding affinity to ESR1 [39]. Indeed, DES disruption of female reproductive tract development and Hoxa10, Hoxa11, and Wnt7a expression is mediated by ESR1 [10].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

WNTs in the Neonatal Mouse Uterus: Potential Regulation of Endometrial Gland Development

Hayashi

Yoshioka

Reardon

et al. 2010

Biology of Reproduction

View full text Add to dashboard Cite

The WNTs are secreted proteins that control essential developmental processes, such as embryonic patterning, cell growth, migration, and differentiation. In mice, three members of the Wnt gene family (Wnt4, Wnt5a, and Wnt7a) have been studied extensively in the female reproductive tract. The present study determined effects of postnatal day and exposure to diethylstilbestrol (DES) on Wnt and Fzd gene expression in the mouse uterus as well as the biological role of Wnt11 in postnatal mouse uterine development and function. Wnt4, Wnt5a, Wnt7a, Wnt7b, Wnt11, Wnt16, Fzd6, and Fzd10 were detected by in situ hybridization in the neonatal mouse uterus. In situ hybridization analyses revealed that Wnt4, Wnt5a, and Wnt16 were localized in the endometrial stroma, whereas Wnt7a, Wnt7b, Wnt11, Fzd6, and Fzd10 were in the uterine epithelia of neonatal mice. Exposure of mice to estrogen or estrogen receptor agonists during critical development periods inhibits endometrial adenogenesis. In the present study, DES-induced disruption of endometrial gland development was associated with reduction or suppression of Wnt4, Wnt5a, Wnt7a, Wnt11, Wnt16, and Fzd10. Ablation of Wnt11, an epithelial-expressed, DES-regulated gene, in the neonatal uterus did not affect endometrial adenogenesis or expression of other Wnt genes. Interestingly, Wnt11-deleted uteri had more endometrial glands on Postnatal Day 10. Although CTNNB1 expression was not affected by ablation of Wnt11, Vangl2 was inhibited in the uteri of Wnt11(d/d) mice. These results support the idea that a number of different Wnt genes are potential regulators for uterine morphogenesis; however, Wnt11 does not have a direct effect on uterine development.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Because most of actions of neonatal DES exposure are mediated through ESR1 [39], we have examined immunoreactive ESR1 in the uteri of DES-treated mice during the neonatal period (Fig. 1C).…”

Section: Effects Of Des Exposure In Neonatal Uterusmentioning

confidence: 99%

WNTs in the Neonatal Mouse Uterus: Potential Regulation of Endometrial Gland Development

Hayashi

Yoshioka

Reardon

et al. 2010

Biology of Reproduction

View full text Add to dashboard Cite

show abstract

“…29 The synthesis of NC-8 through NC-16 is depicted in Schemes 4 and 5. The synthesis of NC-17, N-18, N-19, and NC-20 proceeded via a methyl ester intermediate (18), which was synthesized from triflate 17 via palladium-catalyzed alkoxycarbonylation 49 (Scheme 6). Reaction of ester 18 with boron tribromide resulted in saponification and deprotection of the methyl ethers to give the carboxylic acid derivative NC-17.…”

Section: Resultsmentioning

confidence: 99%

“…We desired a scaffold with a high likelihood of ER activity, for which the pharmacology had not yet been extensively explored, thereby maximizing the likelihood of discovering compounds with novel properties. Several derivatives have already been investigated to circumvent the problems with the 4-hydroxylated triphenylethylene scaffold. − Precedence for our selection of an indene-based scaffold arises from reports of indenestrol A, − a diethylstilbestrol (DES) metabolite which is poorly uterotrophic, but has strong binding affinity for ERα and acts as an agonist at an ERE . Limited SAR studies of 1,3-dialkyl-2-arylindenes have highlighted the importance of the C-3 stereochemistry and the phenolic hydroxyls for binding and activity − and demonstrated a preference for an ethyl substituent at the 3-position of the indene ring .…”

Section: Introductionmentioning

confidence: 99%

“…Several derivatives have already been investigated to circumvent the problems with the 4-hydroxylated triphenylethylene scaffold. − Precedence for our selection of an indene-based scaffold arises from reports of indenestrol A, − a diethylstilbestrol (DES) metabolite which is poorly uterotrophic, but has strong binding affinity for ERα and acts as an agonist at an ERE . Limited SAR studies of 1,3-dialkyl-2-arylindenes have highlighted the importance of the C-3 stereochemistry and the phenolic hydroxyls for binding and activity − and demonstrated a preference for an ethyl substituent at the 3-position of the indene ring . A limited series of basic 2,3-diarylindenes was examined for antifertility properties in rats during the 1960s, , followed by analysis of the binding orientation and fluorescent properties of the 2,3-diarylindenes ,− and limited SAR studies …”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Differential Response of Estrogen Receptor Subtypes to 1,3-Diarylindene and 2,3-Diarylindene Ligands

et al. 2005

View full text Add to dashboard Cite

Estrogen receptors (ERs) control transcription of genes important for normal human development and reproduction. The signaling networks are complex, and there is a need for a molecular level understanding of the roles of receptor subtypes ERalpha and ERbeta in normal physiology and as therapeutic targets. We synthesized two series of ER ligands, based on a common indene scaffold, in an attempt to develop compounds that can selectively modulate ER-mediated transcription. The 3-ethyl-1,2-diarylindenes, utilizing an amide linker for the 1-aryl extension, bind weakly to the ERs. The 2,3-diarylindenes bind with high affinity to the ER subtypes and demonstrate a range of different biological activities, both in transcriptional reporter gene assays and inhibition of estradiol-stimulated proliferation of MCF-7 cells. Several ligands differentiate between ERalpha and ERbeta subtypes at an estrogen response element (ERE), displaying various levels of partial to full agonist activity at ERalpha, while antagonizing estradiol action at ERbeta.

show abstract

Estrogen Regulation of Uterine Proliferation: How Many ERRs Are Required?

Stancel¹,

Boettger‐Tong²,

Chiappetta³

et al. 1995

Molecular and Cellular Aspects of Periimplantation Processes

View full text Add to dashboard Cite

Diethylstilbestrol metabolites and analogs. Biochemical probes for differential stimulation of uterine estrogen responses.

Cited by 35 publications

References 35 publications

WNTs in the Neonatal Mouse Uterus: Potential Regulation of Endometrial Gland Development

WNTs in the Neonatal Mouse Uterus: Potential Regulation of Endometrial Gland Development

Differential Response of Estrogen Receptor Subtypes to 1,3-Diarylindene and 2,3-Diarylindene Ligands

Estrogen Regulation of Uterine Proliferation: How Many ERRs Are Required?

Contact Info

Product

Resources

About