- Synthesis of Dithiolethiones and Identification of Potential Neuroprotective Agents via Activation of Nrf2-Driven Antioxidant Enzymes
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Oxidative stress is implicated in the pathogenesis of a wide variety of neurodegenerative disorders, and accordingly, dietary supplement of exogenous antioxidants or/and upregulation of the endogenous antioxidant defense system are promising for therapeutic intervention or chemoprevention of neurodegenerative diseases. Nrf2, a master regulator of the cellular antioxidant machinery, cardinally participates in the transcription of cytoprotective genes against oxidative/electrophilic stresses. Herein, we report the synthesis of 59 structurally diverse dithiolethiones and evaluation of their neuroprotection against 6-hydroxydopamine-or H2O2-induced oxidative damages in PC12 cells, a neuron-like rat pheochromocytoma cell line. Initial screening identified compounds 10 and 11 having low cytotoxicity but conferring remarkable protection on PC12 cells from oxidative-mediated damages. Further studies demonstrated that both compounds upregulated a battery of antioxidant genes as well as corresponding genes' products. Significantly, silence of Nrf2 expression abolishes cytoprotection of 10 and 11, indicating targeting Nrf2 activation is pivotal for their cellular functions. Taken together, the two lead compounds discovered here with potent neuroprotective functions against oxidative stress via Nrf2 activation merit further development as therapeutic or chemopreventive candidates for neurodegenerative disorders.
- Bai, Feifei,Fang, Jianguo,Song, Zi-Long,Zhang, Baoxin
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p. 2214 - 2231
(2020/03/06)
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- In situ generation of nitrile oxides from copper carbene and tert -butyl nitrite: Synthesis of fully substituted isoxazoles
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Herein, we present a novel [3 + 2] cycloaddition reaction of β-keto esters with nitrile oxides, which were generated in situ from copper carbene and tert-butyl nitrite. This three-component reaction provides new methodology for the direct synthesis of fully substituted isoxazole derivatives, featuring mild reaction conditions, readily accessible starting materials and simple operation. The experimental studies and DFT calculations suggest that the reaction starts with the generation of the key intermediate nitrile oxides, followed by a [3 + 2] cycloaddition reaction of β-keto esters to give the final isoxazole products.
- Chen, Rongxiang,Ogunlana, Abosede Adejoke,Fang, Shangwen,Long, Wenhao,Sun, Hongmei,Bao, Xiaoguang,Wan, Xiaobing
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supporting information
p. 4683 - 4687
(2018/07/06)
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- Efficient Synthesis of Functionalized β-Keto Esters and β-Diketones through Regioselective Hydration of Alkynyl Esters and Alkynyl Ketones by Use of a Cationic NHC–AuICatalyst
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Regioselective hydration of α-alkynyl esters and ketones by using a cationic NHC–AuIcatalyst results in β-keto esters and β-diketones, respectively. Controlled release of water in acetone by aldol self-condensation under the reaction conditions makes acetone as better solvent than 1,4-dioxane/water for the hydration of α-alkynyl esters having sensitive ester moieties.
- Tarigopula, Chandrahas,Thota, Ganesh Kumar,Balamurugan, Rengarajan
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p. 5855 - 5861
(2016/12/18)
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- A one-pot copper(II)-catalyzed tandem synthesis of 2-substituted pyrrolo[1,2-b]pyridazin-4(1H)-ones
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A one-pot copper(II)-catalyzed tandem synthesis of 2-substituted pyrrolo[1,2-b]pyridazin-4(1H)-ones from N-aminopyrroles was developed. This tandem reaction involves a Conrad-Limpach-type reaction, including the thermal condensation of N-aminopyrroles with the carbonyl group of β-oxo esters followed by the cyclization of Schiff base intermediates. Compared to the traditional Conrad-Limpach quinoline synthesis, we herein successfully applied copper(II) as a catalyst in this transformation to furnish 2-substituted pyrrolo[1,2-b]pyridazin-4(1H)-ones for the first time. Most of the substrates bearing electron-donating (EDG) and electron-withdrawing (EWG) groups worked well with this procedure. The corresponding products could be converted directly into diverse pyrrolo[1,2-b]pyridazine for drug discovery and materials science. A copper(II)-catalyzed tandem synthesis of 2-substituted pyrrolo[1,2-b]pyridazin-4(1H)-ones from N-aminopyrroles was developed, and the corresponding products could be converted directly into diverse pyrrolo[1,2-b]pyridazine for drug discovery and materials science.
- Tan, Cun,Xiang, Haoyue,He, Qian,Yang, Chunhao
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supporting information
p. 3656 - 3660
(2015/06/16)
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- Access to β-keto esters by palladium-catalyzed carbonylative coupling of aryl halides with monoester potassium malonates
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New tricks for an old dog: The Pd-catalyzed carbonylative α-arylation of monoethyl potassium malonates with aryl bromides and reactive aryl chlorides provides a simple and direct route to aryl β-ketoesters. Because only stoichiometric amounts of carbon monoxide are employed, the method is ideal for the introduction of carbon isotopes into more complex structures. Copyright
- Korsager, Signe,Nielsen, Dennis U.,Taaning, Rolf H.,Skrydstrup, Troels
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supporting information
p. 9763 - 9766
(2013/09/23)
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- CuSO4-catalyzed diazo decomposition in water: a practical synthesis of β-keto esters
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CuSO4 was found to be an efficient catalyst for the diazo decomposition of β-hydroxy α-diazoesters in water. 1,2-H shift occurred efficiently to give β-keto esters in high yields. No O-H bond insertion products were identified.
- Liao, Mingyi,Wang, Jianbo
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p. 8859 - 8861
(2007/10/03)
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- Structure-activity studies of a series of dipyrazolo[3,4-b:3′,4′-d]pyridin-3-ones binding to the immune regulatory protein B7.1
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The interaction of co-stimulatory molecules on T cells with B7 molecules on antigen presenting cells plays an important role in the activation of naive T cells. Consequently, agents that disrupt these interactions should have applications in treatment of transplant rejection as well as autoimmune diseases. To this end, specific small molecule inhibitors of human B7.1 were identified and characterized. Herein, we report the identification of potent small molecule inhibitors of the B7.1-CD28 interaction. In a high-throughput screen we identified several leads that prevented the interaction of B7.1 with CD28 with activities in the nanomolar to low micromolar range. One of these, the dihydrodipyrazolopyridinone 1, was subsequently shown to bind the V-like domain of human B7.1 at equimolar stoichiometry. With this as a starting point, we report here the synthesis and initial in vitro structure-activity relationships of a series of these compounds.
- Green, Neal J.,Xiang, Jason,Chen, Jing,Chen, Lihren,Davies, Audrey M.,Erbe, Dave,Tam, Steve,Tobin, James F.
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p. 2991 - 3013
(2007/10/03)
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- MEDICINAL COMPOSITION
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The present invention is composed of a pharmaceutical composition for the therapy of nephritis which comprises an amide derivative represented by the following formula [1] or pharmaceutically acceptable salt thereof, as an active ingredient: ???wherein R1 and R2 may be the same or different and each is hydrogen, alkyl which may be substituted, acyl, aryl which may be substituted, or an aromatic heterocyclic group which may be substituted; R3, R4, R5 and R6 may be the same or different and each is hydrogen, halogen, hydroxy, amino which may be substituted, alkyl which may be substituted, alkoxy or nitro and the like; and R7 represents cyclic amino which may be substituted or azabicycloalkylamino which may be substituted. The pharmaceutical composition of the invention is useful for the therapy of nephritis.
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- AMIDE DERIVATIVES AND DRUG COMPOSITIONS
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The present invention is composed of an amide derivative represented by the following formula [1] or pharmaceutically acceptable salt thereof: ???wherein R1 and R2 may be the same or different and each is hydrogen, alkyl which may be substituted, acyl, aryl which may be substituted, or an aromatic heterocyclic group which may be substituted; R3, R4, R5, and R6 may be the same or different and each is hydrogen, halogen, hydroxy, amino which may be substituted, alkyl which may be substituted, alkoxy, or nitro and the like; and R7 represents cyclic amino which may be substituted or azabicycloalkylamino which may be substituted, and a pharmaceutical composition which comprises it as an active ingredient. The compound of the invention is useful as an inhibitor of TGF-β production or an antagonist of TGF-β.
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