- Novel carbamοyloxy analogues of tamoxifen: Synthesis, molecular docking and bioactivity evaluation
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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.
- Fokialakis, Nikolas,Haroutounian, Serkos A.,Kasiotis, Konstantinos M.,Lambrinidis, George
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p. 422 - 428
(2021/10/04)
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- Deoxygenative α-alkylation and α-arylation of 1,2-dicarbonyls
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Construction of C-C bonds at the α-carbon is a challenging but synthetically indispensable approach to α-branched carbonyl motifs that are widely represented among drugs, natural products, and synthetic intermediates. Here, we describe a simple approach to generation of boron enolates in the absence of strong bases that allows for introduction of both α-alkyl and α-aryl groups in a reaction of readily accessible 1,2-dicarbonyls and organoboranes. Obviation of unselective, strongly basic and nucleophilic reagents permits carrying out the reaction in the presence of electrophiles that intercept the intermediate boron enolates, resulting in two new α-C-C bonds in a tricomponent process. This journal is
- Arman, Hadi D.,Dang, Hang T.,Haug, Graham C.,Jin, Shengfei,Larionov, Oleg V.,Nguyen, Viet D.
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p. 9101 - 9108
(2020/09/17)
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- Structure-function relationships of estrogenic triphenylethylenes related to endoxifen and 4-hydroxytamoxifen
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Estrogens can potentially be classified into planar (class I) or nonplanar (class II) categories, which might have biological consequences. 1,1,2-Triphenylethylene (TPE) derivatives were synthesized and evaluated against 17β-estradiol (E2) for their estrogenic activity in MCF-7 human breast cancer cells. All TPEs were estrogenic and, unlike 4-hydroxytamoxifen (4OHTAM) and Endoxifen, induced cell growth to a level comparable to that of E2. All the TPEs increased ERE activity in MCF-7:WS8 cells with the order of potency as followed: E2 > 1,1-bis(4,4′-hydroxyphenyl)-2-phenylbut-1-ene (15) > 1,1,2-tris(4-hydroxyphenyl)but-1-ene (3) > Z 4-(1-(4-hydroxyphenyl)-1- phenylbut-1-en-2-yl)phenol (7) > E 4-(1-(4-hydroxyphenyl)-1-phenylbut-1-en-2- yl)phenol (6) > Z(4-(1-(4-ethoxyphenyl)-1-(4-hydroxyphenyl)but-1-en-2-yl) phenol (12) > 4-OHTAM. Transient transfection of the ER-negative breast cancer cell line T47D:C4:2 with wild-type ER or D351G ER mutant revealed that all of the TPEs increased ERE activity in the cells expressing the wild-type ER but not the mutant, thus confirming the importance of Asp351 for ER activation by the TPEs. The findings confirm E2 as a class I estrogen and the TPEs as class II estrogens. Using available conformations of the ER liganded with 4OHTAM or diethylstilbestrol, the TPEs optimally occupy the 4OHTAM ER conformation that expresses Asp351.
- Maximov, Philipp Y.,Myers, Cynthia B.,Curpan, Ramona F.,Lewis-Wambi, Joan S.,Jordan, V. Craig
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experimental part
p. 3273 - 3283
(2010/09/09)
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- Bibenzyl- and stilbene-core compounds with non-polar linker atom substituents as selective ligands for estrogen receptor beta
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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.
- Waibel, Michael,De Angelis, Meri,Stossi, Fabio,Kieser, Karen J.,Carlson, Kathryn E.,Katzenellenbogen, Benita S.,Katzenellenbogen, John A.
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experimental part
p. 3412 - 3424
(2009/10/23)
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- Synthesis and biological evaluation of stilbene-based pure estrogen antagonists
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The nonsteroidal estrogen diethylstilbestrol can be converted into potent antiestrogens devoid of agonist activity by introduction of side chains with appropriate functional groups. Replacement of one of the ethyl substituents in diethylstilbestrol by side chains with functional groups converted this potent estrogen into pure antiestrogens with the potential for the treatment of breast cancer. These agents completely suppressed estrogen receptor-mediated gene activation and inhibited the growth of estrogen-sensitive MCF-7 breast cancer cells in submicromolar concentrations. The most potent derivative displayed similar activity as fulvestrant (ICI 182,780) in vitro and in the mouse uterine weight test. Obviously, the stilbene structure can act as a substitute for estradiol in the development of pure estrogen antagonists.
- Walter, Georg,Liebl, Renate,Von Angerer, Erwin
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p. 4659 - 4663
(2007/10/03)
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- Antiestrogenically active 1,1,2-tris(4-hydroxyphenyl)alkenes without basic side chain: Synthesis and biological activity
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C2-Alkyl substituted derivatives of the 1,1,2-tris(4-hydroxyphenyl)ethene 3a (alkyl = Me (3b), Et (3c), Prop (3d), But (3e)) were synthesized by reaction of 1,2-bis(4-methoxyphenyl)ethanone with the appropriate alkyl halide, followed by a Grignard reaction with 4-methoxyphenylmagnesium bromide, dehydration with phosphoric acid or hydrobromic acid, and ether cleavage with BBr3. The compounds were tested for estrogen receptor (ER) binding affinity in a competition experiment with radio labeled estradiol ([3H]-E2) and for gene activation on the ER-positive MCF-7-2a cell line. All compounds showed high receptor binding affinity (RBA-value: 3b (52. 1%) > 3a (45.5%) > 3c (29.6%) > 3d (4.03%) > 3e (0.95%)). The tests on hormone dependent MCF-7-2a breast cancer cells, stably transfected with the plasmid EREwtcluc, revealed that all 1,1,2-tris(4-hydroxyphenyl)ethenes antagonized the effect of 1 nM estradiol (E2). The compounds 3b (IC50 = 15 nM) and 3c (IC50 = 10 nM) were equal in their effects to 4-hydroxytamoxifen (4OHT) (IC50 = 7 nM). Agonistic effects were low. Only 3a and 3b activated the luciferase expression (relative activation at 1 μM: 3a 60%; 3b 35%). Despite their highly antagonistic potency, the 1,1,2-tris(4-hydroxyphenyl)ethenes showed only low cytotoxic properties on the hormone sensitive MCF-7 cell line.
- Lubczyk, Veronika,Bachmann, Helmut,Gust, Ronald
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p. 1484 - 1491
(2007/10/03)
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- Antifungal agents. 1. Synthesis and antifungal activities of estrogen-like imidazole and triazole derivatives
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The synthesis of some 2-aryl-1-(4-methoxyphenyl)-1-(1H-imidazol-1-yl)ethane derivatives and related 1H-1,2,4- and 1H-1,3,4-triazoles is described. The molecular structure of new derivatives has been established by 1H NMR spectra and X-ray crystallographic analysis. When tested in solid agar cultures the azole derivatives showed from moderate to potent in vitro antifungal activity against Candida albicans and Candida spp.
- Massa,Di Santo,Retico,Artico,Simonetti,Fabrizi,Lamba
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p. 495 - 502
(2007/10/02)
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- 1,1,2-Triphenylbut-1-enes: Relationship between Structure, Estradiol Receptor Affinity, and Mammary Tumor Inhibiting Properties
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1,1,2-Triphenylbut-1-enes, which are substituted with acetoxy groups on one, two, or three aromatic rings in the para and/or meta positions, were synthesized.The identity of the occurring E and Z isomers were established by 1H NMR spectroscopy.A study on structure-activity relationships was carried out with regard to estradiol receptor affinity and to inhibiting effects on the growth of a postmenopausal human mammary carcinoma implanted in nude mice.The para-substituted compounds generally exhibited a higher receptor affinity and a better antitumor activity than the corresponding meta-substituted ones.The E isomers were superior to the respective Z isomers in those two properties.The tumor-inhibiting effect of the mono-and disubstituted compounds was better than that of the trisubstituted ones.Except for the trisubstituted compounds, they all showed a good correlation between estradiol receptor affinity and antitumor activity.One of the compounds was also tested on the 9,10-dimethylbenzanthracene-induced, hormone-dependent mammary carcinoma of the Spraque-Dawley rat, and the results corresponded to those obtained in the xenograft tumor.
- Schneider, Martin R.,Angerer, Erwin von,Schoenenberger, Helmut,Michel, Ralf Th.,Fortmeyer, H. P.
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p. 1070 - 1077
(2007/10/02)
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- Estrogen receptor based imaging agents. II. Synthesis and receptor binding affinity of side-chain halogenated hexestrol derivatives
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We have synthesized as potential imaging agents for human breast tumors a series of hexestrol analogues bearing the halogens fluorine, chlorine, bromine, and iodine at the terminus of the hexane chain. The binding affinity of these compounds for the estrogen receptor from uterine tissues forms a monotonically decreasing series, starting at 129% of that of estradiol for the fluoro analogue and decreasing to 60% for the iodo analogue. Such a modest decrease in binding affinity is thought to reflect the preference of the receptor for lipophilic groups and for substituents of moderate steric size at this site, parameters which change in opposite directions in the halogen sequence going from fluorine to iodine. Three estrogenic bis(trifluoromethyl)diphenylethylenes, prepared by DuPont, also showed substantial binding affinities for the estrogen receptor. In terms of ease of radiolabeling and high receptor binding selectivity, the compound that appears to be the most promising candidate for a breast tumor imaging agent in these series is the chain terminal fluorohexestrol.
- Goswami,Harsy,Heiman,Katzenellenbogen
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p. 1002 - 1008
(2007/10/02)
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