17α -Substituted analogs of estradiol for the development of fluorescent estrogen receptor ligands

Salman, Mohammad; Reddy, B. Rami; Delgado, Pete; Stotter, Philip L.; Fulcher, Letitia C.; Chamness, Gary C.

doi:10.1016/0039-128x(91)90070-c

Cited by 31 publications

(15 citation statements)

References 21 publications

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“…Our design was also supported by the numerous reports of 17α- phenyl ethynylestradiol derivatives tethered to other molecules such as dendrimers, 18 fluorophores, 19 radioactive and luminescent organometallic complexes, 20-22 Pt(II) fragments, 23 and photo affinity tags, 24 all of which show reasonably high binding affinity for ER. While modeling of a phenyl group onto the end of the ethynyl substituent causes severe interactions with the ERα-estradiol protein structure, X-ray analysis of closely related 17α-phenylvinyl estrogens with ERα shows that when presented with this larger substituent at 17α, the ER unwinds a short helix (helix 8), thereby generating a large pocket that accommodates the phenyl group and provides access to the exterior of the protein.…”

Section: Resultsmentioning

confidence: 56%

Steroidal bivalent ligands for the estrogen receptor: Design, synthesis, characterization and binding affinities

LaFrate

Carlson

Katzenellenbogen

2009

Bioorganic & Medicinal Chemistry

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Steroidal bivalent ligands for the estrogen receptor (ER) were designed using crystal structures of ERα dimers as a template. The syntheses of several 17α-ethynylestradiol-based bivalent ligands with varying linker compositions and lengths are described. The binding affinities of these bivalent ligands for ERα and ERβ were determined. In the two series of bivalent ligands that we synthesized, there is a clear correlation between linker length and binding affinity, both of which reach a maximum at the same tether length. Further studies are underway to explore aspects of bivalent ligand and control compound binding to the ERs and their effects on ER dimer formation; these results will be reported in a subsequent publication.

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Section: Resultsmentioning

confidence: 56%

Steroidal bivalent ligands for the estrogen receptor: Design, synthesis, characterization and binding affinities

LaFrate

Carlson

Katzenellenbogen

2009

Bioorganic & Medicinal Chemistry

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“…Addition of phenyllithium to estrone or a protected estrone gave relatively low yields. [9,10] We attempted to optimize the reaction and to extend it to other aryllithiums (see Scheme 1). The results obtained were described in a preliminary communication whose principal conclusions are summarized below.…”

Section: Resultsmentioning

confidence: 99%

“…It is surprising to note the weakness of the data available in the literature on this subject. [9,10] The first 17a-phenylestradiol was not published until 1991 and 1992 and was obtained in modest yield by the action of phenyl lithium on the protected estrone. Reactivity proved to be poor and substituted phenyls were not investigated.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Receptor Binding, Molecular Modeling, and Proliferative Assays of a Series of 17α‐Arylestradiols

et al. 2003

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A series of new derivatives of estradiol substituted at position 17alpha by various aryls has been synthesized. This was made possible by efficient activation methods for the addition of aryllithiums to the carbonyl group at position 17 of estrone by using tetramethylethylenediamine (TMEDA) or BF3 x OEt2. Their relative binding affinity (RBA) for the alpha and the beta forms of the estrogen receptor (ER) have been measured. All except one of the compounds synthesized had an RBA value of around 10 % which indicates a level of tolerance towards the bulky substituent at position 17. The lipophilicity values measured for these compounds are higher than that found for estradiol (E2). A study of their proliferative/antiproliferative effects was carried out on hormone-dependent (MCF7) and hormone-independent (MDA-MB231) breast cancer cell lines. It is interesting to note that all the compounds are estrogenic. The possibility of easily attaching an iodine at the end of a phenyl spacer opens up a route to new radiopharmaceuticals for use in radioimaging.

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“…The 105 estrogen derivatives used as study material are listed in Tables I–IV along with their observed biological activity in terms of RBA. The relative binding affinity of estrogens was collected from the literature 21–25. These binding affinity determinations, which have often been done by different competitive binding affinity assay methods using different receptor preparation, were all placed on a common “relative binding affinity” RBA scale.…”

Section: Methodsmentioning

confidence: 99%

QSAR study of estrogens with the help of PM3‐based descriptors

Pasha

Srivastava²,

Singh³

2005

Int J of Quantum Chemistry

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Quantum chemical descriptors (⑀ HOMO , ⑀ LUMO , absolute hardness, global softness, chemical potential, and electronegativity) and energy descriptors (Q min , ⌬H f 0 , E T , and E E ) based QSAR study of estrogen derivatives was made with the help of PM3 calculations on WinMOPAC 7.21 software. The observed RBA values of estrogens were taken from the literature. QSAR models were made using different quantum chemical and energy descriptors with the help of multiple linear regression analysis. Regression models indicate that absolute hardness in combination with different energy descriptors provide better correlation between observed relative binding affinity (RBA) and predicted relative binding affinity (PA). Regression models for other quantum chemical descriptors with energy descriptors are not as clear as in the case of absolute hardness. Hardness provides a better picture due to the maximum hardness principle and can be used as a QSAR model for predicting the biological activity of any compound.

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17α -Substituted analogs of estradiol for the development of fluorescent estrogen receptor ligands

Cited by 31 publications

References 21 publications

Steroidal bivalent ligands for the estrogen receptor: Design, synthesis, characterization and binding affinities

Steroidal bivalent ligands for the estrogen receptor: Design, synthesis, characterization and binding affinities

Synthesis, Receptor Binding, Molecular Modeling, and Proliferative Assays of a Series of 17α‐Arylestradiols

QSAR study of estrogens with the help of PM3‐based descriptors

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