76579-69-6Relevant academic research and scientific papers
Novel carbamοyloxy analogues of tamoxifen: Synthesis, molecular docking and bioactivity evaluation
Fokialakis, Nikolas,Haroutounian, Serkos A.,Kasiotis, Konstantinos M.,Lambrinidis, George
, p. 422 - 428 (2021/10/04)
Background: Tamoxifen (TAM), a non-steroidal antiestrogen, constitutes the endocrine treatment of choice against breast cancer. Since its inauguration, substantial effort has been devoted towards the design and synthesis of TAM’s analogues aiming to improve its bioactivity and reveal their structure-activity relationship. Objective: One of the most studied synthetic features of TAM’s structure is the ether side chain, which is strongly related to its positioning into the active site of the Estrogen Receptors (ERα and ERβ). Herein, we present the application of a straightforward route for the efficient synthesis of selected novel carbamoyloxy analogues of TAM and the evaluation of their respective binding affinities to the Estrogen Receptors α and β. Methods: A one-pot reaction was applied for the construction of TAM’s triarylethylene core moiety, which subsequently was derivatized to provide efficiently the target carbamoyloxy analogues of TAM. The Z and E isomers of the latter were separated using RP-HPLC-UV and their binding affinities to ERα and ERβ were measured. Results: Among all compounds synthesized, the dimethyl derivative was determined as the most potent for both receptors, displaying binding affinity values comparable to TAM, though the Z-diethyl analogue maintained substantial affinity to both ERs. The aforementioned results were further studied by theoretical calculations and molecular modelling to delineate a concordance among calculations and biological activity. Conclusion: Approach applied herein permitted the extraction of a useful structure-activity relationship correlation pattern highlighting the importance of a chemically stabilized tamoxifen side chain.
Bibenzyl- and stilbene-core compounds with non-polar linker atom substituents as selective ligands for estrogen receptor beta
Waibel, Michael,De Angelis, Meri,Stossi, Fabio,Kieser, Karen J.,Carlson, Kathryn E.,Katzenellenbogen, Benita S.,Katzenellenbogen, John A.
experimental part, p. 3412 - 3424 (2009/10/23)
A series of structurally simple bibenzyl-diol and stilbene-diol core molecules, structural analogs of the well-known hexestrol and diethylstilbestrol non-steroidal estrogens, were prepared and evaluated as estrogen receptor (ER) subtype-selective ligands. Analysis of their ERα and ERβ binding showed that certain substitution patterns engendered binding affinities that were >100-fold selective for ERβ. When further investigated in cell-based gene transcription assays, some molecules showed similarly high relative transcriptional potency selectivity in favor of ERβ. Interestingly, the most ERβ-selective molecules were those bearing non-polar substituents on one of the internal carbon atoms. These compounds should be useful probes for determining the physiological roles of ERβ, and they might lead to the development of more selective and thus safer pharmaceuticals.
Preparation, Receptor Binding, and Fluorescence Properties of Hexestrol-Fluorophore Conjugates: Evaluation of Site of Attachment, Fluorophore Structure, and Fluorophore-Ligand Spacing
Fevig, Thomas L.,Lloyd, John E.,Zablocki, Jeffery A.,Katzenellenbogen, John A.
, p. 156 - 165 (2007/10/02)
We have undertaken a staged development of certain estrogen-fluorophore conjugates, in order to prepare a fluorescent estrogen suitable for determination of the estrogen receptor content of individual cells.Since non-steroidal estrogens with bulky substituents are often more readily bound by receptor than their steroidal counterparts, we have investigated fluorophore conjugates with derivatives of the non-steroidal estrogen hexestrol ((3R*,4S*)-3,4-bis(4-hydroxyphenyl)hexane).On the basis of the receptor-binding affinity of model compounds, we prepared a prototypical set of three ring- and side-chain-substituted fluorescent hexestrol derivatives, whose binding and fluorescence properties ultimately led to the preparation of a series of side-chain-substituted nitrobenzoxadiazole derivatives.The compounds prepared have binding affinities for the estrogen receptors that range from ca. 1percent to 5percent that of estradiol, and they have very favorable fluorescence characteristics, similar to those of fluorescein.
