- Kinetic diastereomer differentiation in Au(III)- and Bi(III)-catalyzed benzylic arylation: Concise and stereocontrolled synthesis of 2-amino-1,1-diarylalkanes
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Benzylic alcohols carrying an adjacent α-nitro or α-azido group on the alkane chain are converted into syn-1,1-diaryl-2-nitro- and 2-azidoalkanes with electron-rich arenes in stereoselective reactions catalyzed by Bronsted and Lewis acids. Gold(III) chloride and bismuth(III) triflate were found to be especially efficient as catalysts, showing kinetically controlled differentiation in the reactivity of diastereomeric α-substituted benzyl alcohols. Applications to therapeutically relevant syn- and anti- 2-amino-1,1-diarylalkanes are projected.
- Chenard, Etienne,Hanessian, Stephen
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supporting information
p. 2668 - 2671
(2014/06/09)
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- Synthesis and investigations on the oxidative degradation of C3/C5-Alkyl-1,2,4-triarylpyrroles as ligands for the estrogen receptor
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In this study, we synthesized 1,2,4-triarylpyrroles as ligands for the estrogen receptor (ER). Two pyrrole series were prepared with either C3-alkyl or C3/C5-dialkyl residues. Compounds from both series were susceptible to oxidative degradation-dialkylated compounds (t1/2=33-66h) to a higher extent than their monoalkylated congeners (t1/2=140-211h). Nevertheless, stability was sufficient for determination of in vitro ER binding affinity. The most active agonist in hormone-dependent, ERα-positive MCF-7/2a and U2-OS/α cells was 1,2,4-tris(4-hydroxyphenyl)-3-propyl-1H-pyrrole (6d) (MCF-7/2a: EC50=70nM; U2-OS/α: EC50=1.6nM). A corresponding inactivity in U2-OS/β cells demonstrated the high ERα selectivity. This trend was confirmed in a competition experiment using estradiol (E2) and purified hERα and hERβ proteins (relative binding affinity (RBA) calculated for 6d: RBA(ERα)=1.85%; RBA(ERβ) 0.01%). Generally, C3/C5-dialkyl substitution led to reduction of activity, possibly due to lower stability. Triarylpyrroles with C3-alkyl or C3/C5-dialkyl residues were synthesized as ligands for the estrogen receptor (ER). The compounds exhibited transcription activation selectively for ERα but only marginally displaced estradiol from its binding site. The compounds were susceptible to oxidative degradation-dialkylated compounds to a higher extent than their monoalkylated congeners. The reasons for instability were elucidated; thus, by changing the substitution pattern, it will be possible to generate stable triarylpyrroles.
- Schaefer, Anja,Wellner, Anja,Gust, Ronald
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p. 794 - 803
(2012/01/06)
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- 1-(4-Methylphenyl)-2-pyrrolidin-1-yl-pentan-1-one (pyrovalerone) analogues: A promising class of monoamine uptake inhibitors
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Dopamine, serotonin, and norepinephrine are essential for neurotransmission in the mammalian system. These three neurotransmitters have been the focus of considerable research because the modulation of their production and their interaction at monoamine receptors has profound effects upon a multitude of pharmacological outcomes. Our interest has focused on neurotransmitter reuptake mechanisms in a search for medications for cocaine abuse. Herein we describe the synthesis and biological evaluation of an array of 2-aminopentanophenones. This array has yielded selective inhibitors of the dopamine and norepinephrine transporters with little effect upon serotonin trafficking. A subset of compounds had no significant affinity at 5HT1A, 5HT1B, 5HT1C, D1, D2, or D3 receptors. The lead compound, racemic 1-(4-methylphenyl)-2-pyrrolidin-1-yl-pentan-1-one 4a, was resolved into its enantiomers and the S isomer was found to be the most biologically active enantiomer. Among the most potent of these DAT/NET selective compounds are the 1-(3,4-dichlorophenyl)- (4u) and the 1-naphthyl- (4t) 2-pyrrolidin-1-yl-pentan-1-one analogues.
- Meltzer, Peter C.,Butler, David,Deschamps, Jeffrey R.,Madras, Bertha K.
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p. 1420 - 1432
(2007/10/03)
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- PYROVALERONE ANALOGS AND THERAPEUTIC USES THEREOF
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New compounds that bind to monoamine transporters are described. The compounds of the present invention can be racemic or pure R-or S-enantiomers. Certain preferred compounds of the present invention have a high selectively dopamine transporter versus the serotonin transporter. Preferred monoamine transporters for the practice of the present invention include the dopamine transporter, the serotonin transporter and the norepinephrine transporter.
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Page/Page column 44
(2008/06/13)
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- Estrogenic diazenes: Heterocyclic non-steroidal estrogens of unusual structure with selectivity for estrogen receptor subtypes
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Estrogens regulate many biological functions, often acting in a tissue-selective manner. Their tissue-selective action is believed to involve differential estrogen action through the two estrogen receptor (ER) subtypes, ERα and ERβ, as well as differential interaction of the ligand-receptor complexes with promoters and coregulator proteins. In the latter case, selectivity is based on the induction of specific conformations of the ligand-ER complex, conformations that are influenced by the structure of the ligand. Estrogen pharmaceuticals having an ideal balance of tissue-selective activity are being sought for menopausal hormone replacement, breast cancer prevention and therapy, and other actions. To expand on the structural diversity of ER ligands that might show such tissue selectivity, we have prepared a series of diazenes (pyrazines, pyrimidines, and pyridazines) substituted with two to four aryl groups and various short-chain aliphatic substituents. All of the pyrazine and pyrimidines bind to ER, some with high affinity and with a considerable degree of preferential binding to either ERα or ERβ. One pyrimidine and one pyrazine have ERα affinity preferences as high as 23 and 9, respectively, and one pyrimidine has an ERβ affinity preference of 8. The pyridazines, by contrast, are quite polar and have only very low binding affinity for the ER. In cell-based transcription assays, several of the pyrimidines and a pyrazine were found to be considerably more agonistic on ERα than on ERβ. Because these triaryl diazenes have the largest volumes among the ER ligands so far investigated, their high affinity demonstrates the flexibility of the ligand binding pocket of the ERs and its tolerance for large substituents. Thus, these novel heterocyclic ligands expand the repertoire of chemical structures that bind to the estrogen receptor, and they could prove to be useful in elucidating the biological behavior of the two ER subtypes and in forming the basis for new estrogen pharmaceuticals having desirable tissue selectivity.
- Ghosh, Usha,Ganessunker, Deshanie,Sattigeri, Viswajanani J.,Carlson, Kathryn E.,Mortensen, Deborah J.,Katzenellenbogen, Benita S.,Katzenellenbogen, John A.
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p. 629 - 657
(2007/10/03)
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- Synthesis and biological evaluation of a novel series of furans: Ligands selective for estrogen receptor α
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A variety of nonsteroidal systems can function as ligands for the estrogen receptor (ER), in some cases showing selectivity for one of the two ER subtypes, ERα or ERβ. We have prepared a series of heterocycle-based (furans, thiophenes, and pyrroles) ligands for the estrogen receptor and assessed their behavior as ER ligands. An aldehyde enone conjugate addition approach and an enolate alkylation approach were developed to prepare the 1,4-dione systems that were precursors to the trisubstituted and tetrasubstituted systems, respectively. All of the diones were easily converted into the corresponding furans, but formation of the thiophenes and pyrroles from the more highly substituted 1,4-diones was problematical. Of the systems investigated, the tetrasubstituted furans proved to be most interesting. They were ERα bindingand potency-selective agents, with the triphenolic 3-alkyl-2,4,5-tris(4-hydroxyphenyl)furans (15a-d) displaying generally higher subtype binding selectivity than the bisphenolic analogues (15f-i). Binding selectivity for ERα was as high as 50-70-fold, and transcriptional activation studies showed that several members of this series were ERα selective agonists, with the best compound [3-ethyl-2,4,5-tris(4-hydroxyphenyl)furan, 15b] having full transcriptional activity on ERα while being inactive on ERβ. Comparative binding affinity analysis and molecular modeling were used to investigate the preferred binding mode adopted by the furan ligands, which appears to have the C(2) phenol mimicking the important role of the A-ring of estradiol. These ligands should be useful in studying the biological roles of both ERα and ERβ, and they might form the basis for the development of novel estrogen pharmaceuticals.
- Mortensen,Rodriguez,Carlson,Sun,Katzenellenbogen,Katzenellenbogen
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p. 3838 - 3848
(2007/10/03)
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