Synthesis and Biological Evaluation of Cyclopropyl Analogs of the Antiestrogen MER 25

Overacre, L. B.; Magarian, Robert A.

doi:10.1006/bioo.1998.1081

Cited by 6 publications

(5 citation statements)

References 25 publications

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“…They were prepared as 1 ϫ 10 Ϫ2 M stocks in 100% ethanol and stored at Ϫ20°C. Z-1,1-Dichloro-2,3-diphenylcyclopropane (also known as Analog II) and the DTACs were synthesized as described previously (Magarian and Benjamin, 1975;Day et al, 1991;Singh et al, 1996;Overacre and Magarian, 1998), prepared as 1 ϫ 10 Ϫ3 M stocks in DMSO, and stored at Ϫ20°C. Before use in an experiment, each of the ligands was further diluted into the requisite amounts of DMSO and medium to keep vehicle concentrations constant.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of Estrogen Receptor α-Mediated Transcription by Antiestrogenic 1,1-Dichloro-2,2,3-triarylcyclopropanes

Cheng

Kanterewicz²,

Hershberger³

et al. 2004

Mol Pharmacol

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A novel class of pure antiestrogens, 1,1-dichloro-2,2,3-triarylcyclopropanes (DTACs), lack estrogenic activity in a mouse uterotrophic assay and inhibit the growth of estrogen-sensitive MCF-7 breast cancer cells (Day et al., 1991). Here, reporter assays were used to evaluate the effects of the DTACs on estrogen receptor ␣ (ER␣)-mediated transcription from either classic estrogen-response elements (EREs) or nonclassic AP-1 elements. Among the DTACs tested, only the compounds with smaller aromatic substituents, BDRM72 and BDRM81, displayed weak agonist activity on EREs. Their activity was less than that observed for the ER partial agonist, 4-hydroxytamoxifen (ZOHT). In competition experiments, the DTACs blocked estradiol-stimulated transcription from an ERE in a dose-dependent manner and were more effective inhibitors than ZOHT. Each of the DTACs was significantly less active than ZOHT or the pure antiestrogen ICI 182,780 (faslodex) in stimulating transcription from nonclassic AP-1 elements in the presence of ER␣. DTACs did not modulate either basal or TPA (12-O-tetradecanoylphorbol-13-acetate)-stimulated transcription from an AP-1 element in the absence of ER␣, indicating that they are not nonspecific inhibitors of transcription and that ER␣ is the drug target. Glutathione S-transferase pull-down assays were used to examine whether DTACs alter the interaction between ER␣ and the p160 coactivator, GRIP1. BDRM35, which has the same dimethylaminomethoxy and phenolic moieties as ZOHT, reduced binding by more than 50%. Thus, disruption of p160 coactivator recruitment by ER␣ may represent one mechanism by which DTACs function as antiestrogens. BDRM35 also suppresses estradiol induction of endogenous target genes cmyc and cyclin D1 in MCF-7 breast cancer cells.

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Section: Methodsmentioning

confidence: 99%

Inhibition of Estrogen Receptor α-Mediated Transcription by Antiestrogenic 1,1-Dichloro-2,2,3-triarylcyclopropanes

Cheng

Kanterewicz²,

Hershberger³

et al. 2004

Mol Pharmacol

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“…Many examples of gem -dichlorocyclopropanes prepared by the addition of dichlorocarbene to unsaturated compounds have appeared recently. − Some recent examples of reactions of unsaturated hydrocarbons with dichlorocarbene are collected in Table . The superiority of the PTC method is illustrated in eq 6.…”

Section: Syntheses Of Gem -Dihalocyclopropanesmentioning

confidence: 99%

Syntheses ofgem-Dihalocyclopropanes and Their Use in Organic Synthesis

2003

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“…Flexible antiestrogens. structure 22 was reported by the same group as a potent nonsteroidal antiestrogen without intrinsic estrogenic activity and with enhanced estrogen antagonism (nearly complete inhibition at concentration of 1.0 to 100 nM in MCF-7 cells) when compared with tamoxifen [152].…”

Section: Cyclopropyl and Naphthalene Derived Compoundsmentioning

confidence: 99%

Advances in the Science of Estrogen Receptor Modulation

Mj¹,

Dg²

2003

CMC

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This work details recent advances in the science of estrogen receptor (ER) modulation, with emphasis on the discovery of novel ligands for the ER ligand binding domain (LBD). A detailed examination of structural studies of the ERs is presented with analysis of the impact of such works on contemporary ligand design and the molecular pharmacology of the ER. The various classes of ER modulators are discussed on the basis of stuctural similarities including selective estrogen receptor modulators (SERMs) and 'pure' non-steroidal antiestrogens. Additionally we review the emergence of a novel selective class of modulator which we have termed the selective estrogen receptor subtype modulators (SERSMs) and, in a departure from LBD strategies we examine the discovery of novel peptide inhibitors of the ER which inhibit transcriptional activiation of agonist liganded receptor through interaction with coactivator recruitment proteins, and offer unique insight to the mechanism of action of all classes of ER modulators. Through examination of patent and classical literature we present a thorough and informative cross-section of the contemporary state of the art in this exciting field of pharmaceutical research.

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Synthesis and Biological Evaluation of Cyclopropyl Analogs of the Antiestrogen MER 25

Cited by 6 publications

References 25 publications

Inhibition of Estrogen Receptor α-Mediated Transcription by Antiestrogenic 1,1-Dichloro-2,2,3-triarylcyclopropanes

Inhibition of Estrogen Receptor α-Mediated Transcription by Antiestrogenic 1,1-Dichloro-2,2,3-triarylcyclopropanes

Syntheses ofgem-Dihalocyclopropanes and Their Use in Organic Synthesis

Advances in the Science of Estrogen Receptor Modulation

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