- Activation of anti-oxidant Nrf2 signaling by substituted trans stilbenes
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Nrf2, which is a member of the cap'n’ collar family of transcription factors, is a major regulator of phase II detoxification and anti-oxidant genes as well as anti-inflammatory and neuroprotective genes. The importance of inflammation and oxidative stress in many chronic diseases supports the concept that activation of anti-oxidant Nrf2 signaling may have therapeutic potential. A number of Nrf2 activators have entered into clinical trials. Nrf2 exists in the cytosol in complex with its binding partner Keap1, which is a thiol-rich redox-sensing protein. In response to oxidative and electrophilic stress, select cysteine residues of Keap1 are modified, which locks Keap1 in the Nrf2-Keap1 complex and allows newly synthesized Nrf2 to enter the nucleus. Numerous Nrf2-activating chemicals, including a number of natural products, are electrophiles that modify Keap1, often by Michael addition, leading to activation of Nrf2. One concern with the design of Nrf2 activators that are electrophilic covalent modifiers of Keap1 is the issue of selectivity. In the present study, substituted trans stilbenes were identified as activators of Nrf2. These activators of Nrf2 are not highly electrophilic and therefore are unlikely to activate Nrf2 through covalent modification of Keap1. Dose-response studies demonstrated that a range of substituents on either ring of the trans stilbenes, especially fluorine and methoxy substituents, influenced not only the sensitivity to activation, reflected in EC50values, but also the extent of activation, which suggests that multiple mechanisms are involved in the activation of Nrf2. The stilbene backbone appears to be a privileged scaffold for development of a new class of Nrf2 activators.
- Deck, Lorraine M.,Whalen, Lisa J.,Hunsaker, Lucy A.,Royer, Robert E.,Vander Jagt, David L.
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p. 1423 - 1430
(2017/02/18)
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- Inhibitory effect of cytotoxic stilbenes related to resveratrol on the expression of the VEGF, hTERT and c-Myc genes
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A group of thirty-nine stilbene derivatives, prepared by means of Heck coupling reactions, has been investigated for their cytotoxicity, as well as for their ability to inhibit the production of the vascular endothelial growth factor (VEGF) and the activation of telomerase. The ability of these compounds to inhibit proliferation of two tumoral cell lines (HT-29 and MCF-7) and one non tumoral cell line (HEK-293) was first determined. Subsequently, we determined the capacity of the compounds to inhibit the secretion of VEGF in the aforementioned cell lines and to downregulate the expression of the VEGF, hTERT and c-Myc genes, the two latter involved in the control of the activation of telomerase. One of the synthetic stilbenes, (E)-4-(4-methoxystyryl)aniline, showed strong cytotoxicity and proved able to cause a marked decrease both in the secretion of VEGF and in the expression of the hTERT and c-Myc genes, in all cases at concentrations in the low nanomolar range.
- Martí-Centelles, Rosa,Falomir, Eva,Murga, Juan,Carda, Miguel,Marco, J. Alberto
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supporting information
p. 488 - 496
(2015/10/05)
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- Syntheses of polyfunctionalized resveratrol derivatives using Wittig and Heck protocols
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Improved protocols for Wittig reaction and palladium-catalyzed Heck coupling give expedient access to a series of unprecedented polyfunctionalized artificial-resveratrol derivatives. In the modified Wittig protocol, trimethylsilyl was used as a highly valuable protective group of the phenolic functions of starting aromatic materials. A clean O-alkylation of hydroxylated stilbenes with ethylene carbonate was also conducted. Thus, Wittig reaction followed by hydroxyethylation take place one-pot with only carbon dioxide as waste. Additionally, a palladium-catalyzed Heck coupling strategy was developed by using ferrocenyl phosphane ligands, and multi-functionalized hydroxylated stilbenes were obtained without the need of any protection/deprotection sequence. Up to six functional groups are introduced by these procedures, which limit the number of reactions steps, the waste toxicity, and the use of costly reagents.
- Chalal, Malik,Vervandier-Fasseur, Dominique,Meunier, Philippe,Cattey, Hélène,Hierso, Jean-Cyrille
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experimental part
p. 3899 - 3907
(2012/07/14)
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- Quinone reductase induction activity of methoxylated analogues of resveratrol
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Agents that induce the activity of phase II enzymes play an important role in intervening with the carcinogenic process at the initiation stage. Resveratrol is well known for its chemopreventive activity against major stages of carcinogenesis. In this study, several methoxylated analogues of resveratrol were synthesized and evaluated for their ability to induce the activity of the phase II enzyme quinone reductase (QR). Methoxy groups serve to increase lipophilicity and improve metabolic stability. Compared to resveratrol, analogues with ortho-methoxy substituents were found to be more potent inducers of QR and to exert their activity in a qualitatively different manner. The greater induction activities associated with these stilbenoids serve as a useful starting point for the design of improved chemopreventive agents.
- Zhang,Go
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p. 841 - 850
(2008/02/12)
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- Synthesis, antitumor evaluation, and apoptosis-inducing activity of hydroxylated (E)-stilbenes
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The parallel solution-phase synthesis of a series of 30 monohydroxylated (E)-stilbene analogues is described. In vitro screening revealed low micromolar activity (GI50) against the MDA MB 468 breast cancer cell line. Activity in MDA MB 468 cells correlated with the ability to induce apoptosis following drug treatment by the most potent agents in the series, e.g., 5dy and 5jy, an observation further reinforced by Annexin V-FITC analysis and fluorescence microscopy.
- Lion, Cedric J.,Matthews, Charles S.,Stevens, Malcolm F. G.,Westwell, Andrew D.
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p. 1292 - 1295
(2007/10/03)
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- SYNTHESE DE CETONES SPIRANNIQUES TRICYCLIQUES DERIVEES DE PRODUITS NATURELS
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In SbF5-HF compound 10a is unreactive whereas esters 10b and 10c cyclize to enones 18 (b or c) and 19 (b or c).Protonation of the esters groups prevents the corresponding aromatic ring protonation and deactivation which is observed with phenol 10a.Spiroke
- Berrier, Christian,Jacquesy, Jean-Claude,Renoux, Alain
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p. 212 - 218
(2007/10/02)
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