New biospecific adsorbents for the purification of estradiol receptor.

Bucourt, R.; Vignau, M; Torelli, V.

doi:10.1016/s0021-9258(17)34385-5

Cited by 116 publications

(30 citation statements)

References 13 publications

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“…Introduction of the 7α-side chain was thus accomplished by a less direct but versatile synthetic pathway via Cu()-promoted conjugate-addition of 9-(dimethyl-tert-butylsilyloxy)nonylmagnesium bromide to 17β-hydroxyestra-4,6-dien-3-one (1). 29,12 This approach is however non-stereoselective, leading to a mixture of 7α-β-epimers that were separated by flash chromatography (the 7α-isomer 2 is the major and less polar compound and the 7β-isomer is the minor and more polar product). 12,14 Another disadvantage of this approach is the requirement of the A-ring aromatization step, which is accomplished after protecting the side-chain terminus as an acetate.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of 16α-fluoro ICI 182,780 derivatives: powerful antiestrogens to image estrogen receptor densities in breast cancer by positron emission tomography

Seimbille

Bénard

Lier

2002

J. Chem. Soc., Perkin Trans. 1

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We prepared a new series of 7α-substituted derivatives of 16α-fluoroestradiol, based on the very potent antiestrogen 7α-{9- [(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl}-estra-1,3,5(10)-triene-3,17β-diol (ICI 182,780; Faslodex). The latter consist of estradiol functionalized with a side chain at the 7α-position, conferring interesting pharmaceutical properties for endocrine therapy of estrogen receptor (ER) positive breast cancer. The considerable advantages of ICI 182,780 over other selective ER-modulators (SERMs) already used in hormonal therapy, lead us to develop three new 16α-fluoro derivatives with potential use in positron emission tomography (PET), for the imaging of ER densities in breast tumors. Introduction of the long side chain at the 7α-position was accomplished by Cu()promoted conjugate addition of a Grignard reagent to 6-dehydro-19-nortestosterone. Subsequent oxidation of the 17-hydoxy group and A-ring aromatization gave a 7α-substituted estrone derivative. Further addition to complete the side chain gave the ICI 182,780 mimics that were converted to the reactive 16β,17β-cyclic sulfates, i.e. the key intermediates for the 18 F-labeling reaction. Opening of the cyclic sulfates via nucleophilic fluorination with Me 4 NF, followed by rapid hydrolysis in acidic ethanol of the protecting ether and sulfate groups, yielded the desired 16αfluoro PET derivatives of ICI 182,780. The latter procedure is readily adapted for radiolabeling with 18 F by substituting Me 4 NF for 18 F Ϫ in acetonitrile.

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Section: Resultsmentioning

confidence: 99%

Synthesis of 16α-fluoro ICI 182,780 derivatives: powerful antiestrogens to image estrogen receptor densities in breast cancer by positron emission tomography

Seimbille

Bénard

Lier

2002

J. Chem. Soc., Perkin Trans. 1

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“…The effectiveness of the method is determined by the following features: First, the biotinylated steroid bound to agarose-linked streptavidin was not released from the gel because of the exceptionally strong noncovalent binding of biotin to streptavidin. This is in contrast to related affinity chromatography adsorbents, which were developed for the purification of steroid receptors (13,14). These reports emphasized difficulties of washing adsorbents sufficiently well to remove free, unbound steroid hormone.…”

Section: Discussionmentioning

confidence: 98%

Synthesis of 17β-Hydroxyandrost-4-en-3-one−7α-(Biotinyl-6-N-hexylamide), a Conjugate Useful for Affinity Chromatography and for Testosterone Immunoassays

et al. 1996

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We describe the synthesis of 17 beta-hydroxyandrost-4-en-3-one-7 alpha-(biotinyl-6-N-hexylamide) from 17 beta-hydroxyandrost-4-en-3-one (testosterone) via copper-catalyzed 1,6 Michael addition of a 6-(tertbutyldimethylsilyloxyhexyl) chain to 6-dehydrotestosterone 17 beta-acetate. After chromatographic separation of the 7 alpha-isomer from the alpha / beta mixture and cleavage of the silyl ether, the alcohol was oxidized to the 6-hexanal side chain and then subjected to reductive amination. The resulting primary amine is easily biotinylated using biotinyl-N-hydroxysuccinimide ester. The overall yield for the epimeric 7 alpha-end product was 30%. The absolute configurations of the epimers were investigated by 1H NMR studies by the nuclear Overhauser effect. We introduced a biotin label to the testosterone molecule at ring position 7 in compliance with Landsteiner's principle, which states that antibody specificity is directed primarily at that portion of the hapten furthest from the functional group linking it to the carrier protein. Thus, this negligible alteration in comparison to the structure of the respective testosterone hapten used to elicit antibodies offers the feasibility of applying the testosterone derivative as an optimal immunoadsorbent in affinity chromatography. The 7 alpha-biotinylated testosterone was used to obtain active antitestosterone antibodies from a specific antiserum by affinity chromatography. This was achieved by attaching the biotinylated testosterone to agarose-coupled streptavidin beads. Accordingly, a 3H-testosterone-binding test demonstrated a 20-fold increase in affinity of the purified antibody to the steroid compared to the original antiserum, and a recovery of > 80% could be obtained. The antitestosterone antibody, obtained by that method, is an effective component for use in a competitive immunoassay for testosterone in human sera. An assay configuration is conceivable with the same 7 alpha-biotinylated testosterone employed as tracer in combination with a streptavidin-linked reporter enzyme.

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“… , Bucourt et al continued to use the long aliphatic chain located at different positions of estradiol to explore appropriate absorbents on the column. Compared to other positions, such as C2, C3, C4, C17α, and C17β, estradiol-C7α derivatives showed higher stability, binding specificity, and selectivity and were selected for the purification of ER . Later, in 1988, the ICI pharmaceutical company (now AstraZeneca) started to investigate the antagonist effect of steroidal ER ligands.…”

Section: Recent Development Of Serdsmentioning

confidence: 99%

“…Compared to other positions, such as C2, C3, C4, C17α, and C17β, estradiol-C7α derivatives showed higher stability, binding specificity, and selectivity and were selected for the purification of ER. 86 Later, in 1988, the ICI pharmaceutical company (now AstraZeneca) started to investigate the antagonist effect of steroidal ER ligands. ICI 163,964 (7) showed dose-dependent antiestrogenic action effects when coadministered with estradiol, but its antagonist potency was reduced significantly after oral dosing compared to parenteral injection.…”

Section: Role Of Erα In the Mechanism Of Acquiredmentioning

confidence: 99%

“…87−89 Bucourt et al reported the addition of a decamethylene group to the 7α position of E 2 that did not reduce the binding affinity for estrogen receptor. 86 This finding led to a comprehensive medicinal chemistry effort to identify antiestrogenic compounds via the modification of long alkyl chains at the 7α position of E 2 . ICI 182,780, now known as fulvestrant (4), was then discovered and approved by the FDA in 2002 for advanced ER positive breast cancer.…”

Section: Role Of Erα In the Mechanism Of Acquiredmentioning

confidence: 99%

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Selective Estrogen Receptor Degraders (SERDs): A Promising Strategy for Estrogen Receptor Positive Endocrine-Resistant Breast Cancer

Liu

2020

J. Med. Chem.

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Estrogen receptor (ER) plays important roles in gene transcription and the proliferation of ER positive breast cancers. Selective modulation of ER has been a therapeutic target for this specific type of breast cancer for more than 30 years. Selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) have been demonstrated to be effective therapeutic approaches for ER positive breast cancers. Unfortunately, 30−50% of ER positive tumors become resistant to SERM/AI treatment after 3−5 years. Fulvestrant, the only approved selective estrogen receptor degrader (SERD), is currently an important therapeutic approach for the treatment of endocrine-resistant breast cancers. The poor pharmacokinetic properties of fulvestrant have inspired the development of a new generation of oral SERDs to overcome drug resistance. In this review, we describe recent advances in ERα structure, functions, and mechanisms of endocrine resistance and summarize the development of oral SERDs in both academic and industrial areas.

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New biospecific adsorbents for the purification of estradiol receptor.

Cited by 116 publications

References 13 publications

Synthesis of 16α-fluoro ICI 182,780 derivatives: powerful antiestrogens to image estrogen receptor densities in breast cancer by positron emission tomography

Synthesis of 16α-fluoro ICI 182,780 derivatives: powerful antiestrogens to image estrogen receptor densities in breast cancer by positron emission tomography

Synthesis of 17β-Hydroxyandrost-4-en-3-one−7α-(Biotinyl-6-N-hexylamide), a Conjugate Useful for Affinity Chromatography and for Testosterone Immunoassays

Selective Estrogen Receptor Degraders (SERDs): A Promising Strategy for Estrogen Receptor Positive Endocrine-Resistant Breast Cancer

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