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Suqing Zheng,
Y R Santosh Laxmi, Emilie David,
Albena T Dinkova-Kostova,
Katherine H Shiavoni,
Yanqing Ren,
Ying Zheng,
Isaac Trevino,
Ronald Bumeister,
Iwao Ojima,
W Christian Wigley,
James B Bliska,
Dale F Mierke,
Tadashi Honda
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ABSTRACT: Novel monocyclic cyanoenones examined to date display unique features regarding chemical reactivity as Michael acceptors and biological potency. Remarkably, in some biological assays, the simple structure is more potent than pentacyclic triterpenoids (e.g., CDDO and bardoxolone methyl) and tricycles (e.g., TBE-31). Among monocyclic cyanoenones, 1 is a highly reactive Michael acceptor with thiol nucleophiles. Furthermore, an important feature of 1 is that its Michael addition is reversible. For the inhibition of NO production, 1 shows the highest potency. Notably, its potency is about three times higher than CDDO, whose methyl ester (bardoxolone methyl) is presently in phase III clinical trials. For the induction of NQO1, 1 also demonstrated the highest potency. These results suggest that the reactivity of these Michael acceptors is closely related to their biological potency. Interestingly, in LPS-stimulated macrophages, 1 causes apoptosis and inhibits secretion of TNF-α and IL-1β with potencies that are higher than those of bardoxolone methyl and TBE-31.
Journal of Medicinal Chemistry 04/2012; 55(10):4837-46. · 4.80 Impact Factor
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ABSTRACT: To explore more potent N-acylimidazole analogues of CDDO than CDDO-Im, which is one of the most potent compounds in several widely used bioassays related to protection against inflammation and carcinogenesis; we have synthesized and evaluated five new N-acyl(acetylenic)imidazole analogues. Among them, 4-ethynylimidazole 4 is nearly equivalent to CDDO-Im in potency in these bioassays. Remarkably, the solid form of 4 is more stable than that of CDDO-Im. These findings suggest that 4 is a very promising anti-inflammatory and cytoprotective agent and its further preclinical evaluation is warranted.
Bioorganic & medicinal chemistry letters 03/2011; 21(8):2188-91. · 2.65 Impact Factor
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Tadashi Honda,
Hidenori Yoshizawa,
Chitra Sundararajan, Emilie David,
Marc J Lajoie,
Frank G Favaloro,
Tomasz Janosik,
Xiaobo Su,
Yukiko Honda,
Bill D Roebuck,
Gordon W Gribble
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ABSTRACT: Forty-four novel tricycles containing nonenolizable cyano enones (TCEs) were designed and synthesized on the basis of a semisynthetic pentacyclic triterpenoid, bardoxolone methyl, which is currently being developed in phase II clinical trials for the treatment of severe chronic kidney disease in diabetic patients. Most of the TCEs having two different kinds of nonenolizable cyano enones in rings A and C are highly potent suppressors of induction of inducible nitric oxide synthase stimulated with interferon-γ and are highly potent inducers of the cytoprotective enzymes heme oxygenase-1 and NAD(P)H:quinone oxidoreductase-1. Among these compounds, (±)-(4bS,8aR,10aS)-10a-ethynyl-4b,8,8-trimethyl-3,7-dioxo-3,4b,7,8,8a,9,10,10a-octahydrophenanthrene-2,6-dicarbonitrile ((±)-31) is the most potent in these bioassays in our pool of drug candidates including semisynthetic triterpenoids and synthetic tricycles. These facts strongly suggest that an essential factor for potency is not a triterpenoid skeleton but the cyano enone functionality. Notably, TCE 31 reduces hepatic tumorigenesis induced with aflatoxin in rats. Further preclinical studies and detailed mechanism studies on 31 are in progress.
Journal of Medicinal Chemistry 03/2011; 54(6):1762-78. · 4.80 Impact Factor
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Albena T Dinkova-Kostova,
Paul Talalay,
John Sharkey,
Ying Zhang,
W David Holtzclaw,
Xiu Jun Wang, Emilie David,
Katherine H Schiavoni,
Stewart Finlayson,
Dale F Mierke,
Tadashi Honda
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ABSTRACT: The Keap1/Nrf2/ARE pathway controls a network of cytoprotective genes that defend against the damaging effects of oxidative and electrophilic stress, and inflammation. Induction of this pathway is a highly effective strategy in combating the risk of cancer and chronic degenerative diseases, including atherosclerosis and neurodegeneration. An acetylenic tricyclic bis(cyano enone) bearing two highly electrophilic Michael acceptors is an extremely potent inducer in cells and in vivo. We demonstrate spectroscopically that both cyano enone functions of the tricyclic molecule react with cysteine residues of Keap1 and activate transcription of cytoprotective genes. Novel monocyclic cyano enones, representing fragments of rings A and C of the tricyclic compound, reveal that the contribution to inducer potency of the ring C Michael acceptor is much greater than that of ring A, and that potency is further enhanced by spatial proximity of an acetylenic function. Critically, the simultaneous presence of two cyano enone functions in rings A and C within a rigid three-ring system results in exceptionally high inducer potency. Detailed understanding of the structural elements that contribute to the reactivity with the protein sensor Keap1 and to high potency of induction is essential for the development of specific and selective lead compounds as clinically relevant chemoprotective agents.
Journal of Biological Chemistry 10/2010; 285(44):33747-55. · 4.77 Impact Factor
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ABSTRACT: 2-Cyano-3,10-dioxooleana-1,9(11)-dien-28-oic acid anhydride (CDDO anhydride) has been synthesized, which is the first example of an oleanane triterpenoid anhydride. CDDO anhydride shows potency similar to or higher than the corresponding acid (CDDO) in various in vitro and in vivo assays related to inflammation and carcinogenesis. Notably, preliminary phamacokinetics studies show that CDDO anhydride levels are higher than CDDO levels in mouse tissues and blood. Further evaluation of CDDO anhydride is in progress.
Bioorganic & medicinal chemistry letters 02/2010; 20(7):2275-8. · 2.65 Impact Factor
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Jean-Florent Lamarque,
Christophe Lamarque,
Sandrine Lassara,
Maurice Mé Debielle,
Jé Rome Molette, Emilie David,
Sté Phane Pellet-Rostaing,
Marc Lemaire,
Etsuji Okada,
Dai Shibata,
Guillaume Pilet
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ABSTRACT: journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues. Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. In most cases authors are permitted to post their version of the article (e.g. in Word or Tex form) to their personal website or institutional repository. Authors requiring further information regarding Elsevier's archiving and manuscript policies are encouraged to visit: http://www.elsevier.com/copyright Author's personal copy Copper catalyzed 1,3-dipolar cycloaddition reaction of azides with N-(2-trifluoroacetylaryl)propargylamines A mild entry to novel 1,4-disubstituted-[1,2,
Journal of Fluorine Chemistry 01/2008; 129:788. · 2.03 Impact Factor
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Jérémie Fournier Dit Chabert,
Béatrice Marquez,
Luc Neville,
Lionel Joucla,
Sylvie Broussous,
Pascale Bouhours, Emilie David,
Stéphane Pellet-Rostaing,
Bernard Marquet,
Nicole Moreau,
Marc Lemaire
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ABSTRACT: The synthesis based on palladium catalytic coupling of 38 new-arylated benzo[b]thiophenes or thiophenes is described in a few steps. We also report the direct arylation of the position 3 of the benzo[b]thiophenic structure, a 'one pot' 2,5-heterodiarylation of thiophenes as well as the synthesis of precursors of amino-acids with a 2-arylated benzo[b]thiophene core. These compounds were evaluated on bacteria strains: most of them did not exhibit any antibiotic activity but were found to selectively inhibit the NorA multidrug transporter of Staphylococcus aureus. As such, they restored the activity of the NorA substrates ciprofloxacin against a resistant S. aureus strain in which this efflux pump is over-expressed.
Bioorganic & Medicinal Chemistry 08/2007; 15(13):4482-97. · 2.92 Impact Factor
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ABSTRACT: [reaction: see text] Benzo[b]thiophene derivatives are important in part because of their use as selective estrogen receptor modulators. They are usually synthesized by intramolecular cyclization. Here, we propose a method for the synthesis of 2-arylbenzo[b]thiophenes with heteroatoms at the 3-positions directly from the benzo[b]thiophene core by using an aromatic nucleophilic substitution reaction and Heck-type coupling. This methodology provides 2-aryl-3-amino or phenoxybenzo[b]thiophenes in about 35% overall yield in 5 steps.
The Journal of Organic Chemistry 05/2005; 70(9):3569-73. · 4.45 Impact Factor
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Jean-Florent Lamarque,
Christophe Lamarque,
Sandrine Lassara,
Maurice Medebielle,
Jerome Molette, Emilie David,
Stephane Pellet-Rostaing,
Marc Lemaire,
Etsuji Okada,
Dai Shibata,
Guillaume Pilet
129:788-798.
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Tetrahedron Letters 49(11):1860-1864. · 2.68 Impact Factor
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Tetrahedron. 60(14):3221-3230.
