Synthesis of 17α-ethynyl-7α,11β-dihydroxyestra-1,3,5(10)-triene-3,17β-diol

Burdett, James E.; Rao, P. Nageswara; Kim, Hyun Koo; Karten, Marvin T.; Blye, Richard P.

doi:10.1039/p19820002877

Cited by 9 publications

(4 citation statements)

References 3 publications

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“…As shown in Scheme 3, treatment of 2-ethoxy-6-oxoestradiol diacetate (43) (Cushman et al, 1997) with triflic anhydride under basic conditions afforded the enol triflate 48, which was reduced in the presence of formic acid, triethylamine, triphenylphosphine, and palladium acetate in DMF to afford the cyclic alkene 33 (Ciattini et al, 1990). Instead of the expected 6␣,7␣-epoxide, oxidation of 33 with m-chloroperbenzoic acid gave compounds 49 and 50, which are the addition products of m-chloroperbenzoic acid to the 6␣,7␣-epoxide (Burdett et al, 1982). The stereochemical assignments are based on the larger axial-equatorial coupling observed between the C-6 and C-7 methine protons in 49 (J ϭ 3.5 Hz) versus the smaller diequatorial coupling constant (J ϭ 2.2 Hz) seen with 50 (Jackman and Sternhell, 1969).…”

Section: Synthetic Chemistrymentioning

confidence: 99%

2-Methoxyestradiol and Analogs as Novel Antiproliferative Agents: Analysis of Three-Dimensional Quantitative Structure-Activity Relationships for DNA Synthesis Inhibition and Estrogen Receptor Binding

et al. 2002

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2-Methoxyestradiol (2-MEO), a metabolite of estrogen, is an attractive lead compound for the development of novel antitumor and anti-inflammatory agents, because it embodies antiproliferative and antiangiogenic activities in one molecule. However, the affinity of 2-MEO for the estrogen receptor would lead to undesirable side effects. As a prelude to the design of 2-MEO-like compounds with an optimal activity profile, we assayed 2-MEO and a series of analogs for their ability to cause G 1 cell-cycle arrest (by measuring inhibition of DNA synthesis in human cultured airway smooth muscle) and to inhibit binding of [ 3 H]estradiol at the estrogen receptor (ER; from rat uterine smooth muscle). One compound, a diacetoxy enediol derivative, was identified with reasonable potency for DNA synthesis (pIC 50 ϭ 5.97) but showed negligible affinity for the ER (pIC 50 Ͻ 5). Three-dimensional quantitative structure-activity relationships were developed for these activities using comparative molecular field analysis (CoMFA) techniques. Comparison of optimized CoMFA models revealed distinct structural requirements for DNA synthesis inhibition and ER binding. For example, DNA synthesis inhibition is enhanced by electropositive substitutions in the 2-position below the plane of the steroid A-ring, whereas ER binding is favored by electronegative substitution in this position. Similarly, DNA synthesis inhibition correlates negatively with increased steric bulk in regions clustered around the A and B rings; changes in steric bulk in these regions has little correlation with ER binding. These observations will guide the design of new analogs with improved potency for desired characteristics (e.g., DNA synthesis inhibition) with minimal unwanted activities (e.g., ER binding).Interest in the metabolites of estrogen has grown in the last decade, because it has been appreciated that a number of the actions of this sex hormone may be caused by biologically active metabolites. For example, the glucuronides of estrogen and its metabolites cause cholestatic jaundice (Zhu et al., 1996), whereas the catecholestrogens are implicated in the association between estrogen and increased incidence of certain tumors (Zhu and Conney, 1998). The cardioprotective effects of estrogen have been ascribed to an interaction between estrogen and the high-affinity estrogen receptor (ER); recent evidence suggests that the cardioprotective effects of estrogen are mediated largely, if not exclusively, via the ER␣ subtype (Brouchet et al., 2001;Hodgin et al., 2001). Alternative lower affinity receptors that bind estrogen have been described, but these do not seem to interact with physiological levels of estrogen, opening up the possibility that a related ligand binds and activates these receptors under physiological conditions (Eriksson et al., 1980). 2-Methoxyestradiol (2-MEO, compound 1; Table 1), once regarded as an inactive metabolite of estrogen, has been identified as an inhibitor of the proliferation of a variety of cell types and as an antiangiogen...

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Section: Synthetic Chemistrymentioning

confidence: 99%

2-Methoxyestradiol and Analogs as Novel Antiproliferative Agents: Analysis of Three-Dimensional Quantitative Structure-Activity Relationships for DNA Synthesis Inhibition and Estrogen Receptor Binding

et al. 2002

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“…Completion of the synthesis of cycloepoxydon required regio- and diastereoselective epoxidation of epoxyquinol 10 (Scheme ). Although electrophilic epoxidations of conjugated dienone substrates generally provide γ,δ-epoxy enones, the hydroxyl-directing group effects of 10 were unclear at the outset. In the event, treatment of 10 with m -CPBA cleanly afforded γ,δ-epoxy enone 11 .…”

mentioning

confidence: 99%

Total Synthesis of the NF-κB Inhibitor (−)-Cycloepoxydon: Utilization of Tartrate-Mediated Nucleophilic Epoxidation

Pace

Liang

et al. 2001

J. Am. Chem. Soc.

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“…The introduction of the 7αhydroxy group was accomplished by reduction of the 6,7epoxide 120. Access to the estrane series was given through aromatization with Zn/DMF (concomitant loss of C18 methyl) [99].…”

Section: E) Heteroatom Functionalization At C7mentioning

confidence: 99%

C7-Substituted Estranes and Related Steroids

Morais¹,

Yoshioka²,

Watanabe³

et al. 2006

MROC

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Synthesis of 17α-ethynyl-7α,11β-dihydroxyestra-1,3,5(10)-triene-3,17β-diol

Abstract: Die Titelverbindung (VII) wird ausgehend vom Trion (I), wie im Schema aufgezeichnet, synthetisiert.

Cited by 9 publications

References 3 publications

2-Methoxyestradiol and Analogs as Novel Antiproliferative Agents: Analysis of Three-Dimensional Quantitative Structure-Activity Relationships for DNA Synthesis Inhibition and Estrogen Receptor Binding

2-Methoxyestradiol and Analogs as Novel Antiproliferative Agents: Analysis of Three-Dimensional Quantitative Structure-Activity Relationships for DNA Synthesis Inhibition and Estrogen Receptor Binding

Total Synthesis of the NF-κB Inhibitor (−)-Cycloepoxydon: Utilization of Tartrate-Mediated Nucleophilic Epoxidation

C7-Substituted Estranes and Related Steroids

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