- The discovery, design and synthesis of potent agonists of adenylyl cyclase type 2 by virtual screening combining biological evaluation
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Adenylate cyclases (ACs), play a critical role in the conversion of adenosine triphosphate (ATP) into the second messenger cyclic adenosine monophosphate (cAMP). Studies have indicated that adenylyl cyclase type 2 (AC2) is potential drug target for many diseases, however, up to now, there is no AC2-selective agonist reported. In this research, docking-based virtual screening with the combination of cell-based biological assays have been performed for discovering novel potent and selective AC2 agonists. Virtual screening disclosed a novel hit compound 8 as an AC2 agonist with EC50 value of 8.10 μM on recombinant human hAC2 + HEK293 cells. The SAR (structure activity relationship) based on the derivatives of compound 8 was further explored on recombinant AC2 cells and compound 73 was found to be the most active agonist with the EC50 of 90 nM, which is 160-fold more potent than the reported agonist Forskolin and could selectively activate AC2 to inhibit the expression of Interleukin-6. The discovery of a new class of AC2-selective agonists would provide a novel chemical probe to study the physiological function of AC2.
- Li, Shanshan,Song, Gao,Wang, Liang-Liang,Weng, Zhiying,Xu, Guowei,Yang, Weimin,Yang, Yanming,Yang, Yaqing,Zhang, Jiajun,Zuo, Zhili
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supporting information
(2020/02/27)
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- Preparation method of heat-resistant modifier N-tert-butyl maleimide
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The invention discloses a preparation method of a heat-resistant modifier N-tert-butyl maleimide. The preparation method comprises the following steps: firstly, adding acetone and maleic anhydride into a reaction container, and stirring for dissolving; then dropwise adding mixed liquid of tert-butylamine and acetone, and heating for reaction to obtain N-tert-butyl maleamic acid; heating an obtained reaction solution, and adding a polymerization inhibitor and a sulfoxide chloride solution for reaction; after reaction, heating an obtained reaction solution, slowly dropwise adding N,N-dimethylaniline, and after dropwise adding, preserving heat for reaction; after reaction, adding warm water into an obtained reaction product respectively for performing liquid separation for three times; heating for concentrating liquid obtained after liquid separation, recycling an acetone solvent, and collecting a fraction, namely the product N-tert-butyl maleimide. According to the preparation method, the reaction operation is convenient, used raw materials are simple and easy to obtain, the product quality is stable, and the industrial production is easy; when the preparation method provided by theinvention is used for preparing a target product, the overall cost is significantly reduced and a large amount of waste liquid is avoided; therefore, the preparation method has significant economic and social benefits.
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Paragraph 0052-0057; 0062-0067; 0072-0077; 0082-0087
(2018/03/26)
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- Cavity-promoted Diels - Alder reactions of unsubstituted naphthalene: Fine reactivity tuning by cavity shrinkage
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By finely tuning the cavity volume of a coordination cage, the Diels - Alder reactivity of aromatic compounds was enhanced. Even unsubstituted naphthalene could be made to undergo the Diels - Alder reaction with N-tert-butylmaleimide, with perfectly controlled syn-selectivity. M6L4 cages with standard and contracted cavities had opposite effects on the reaction: the former favored larger Diels - Alder substrates, whereas the latter favored smaller ones.
- Fang, Yu,Murase, Takashi,Fujita, Makoto
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supporting information
p. 1095 - 1097
(2015/09/02)
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- Visible light mediated cyclization of tertiary anilines with maleimides using nickel(II) oxide surface-modified titanium dioxide catalyst
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Surface-modified titanium dioxides by highly dispersed NiO particles have an extended absorption in the visible light region and a reduced hole-electron pair recombination than unmodified TiO2. They have now been successfully applied as highly active heterogeneous photocatalysts in the visible light mediated direct cyclization of tertiary anilines with maleimides to give tetrahydroquinoline products in moderate to high yields at ambient temperature. In contrast with unmodified titanium dioxide catalysts that are conventionally used in a stoichiometric amount in combination with UVA light, only a catalytic amount (1 mol %) of the surface-modified TiO2 catalyst is needed along with visible light to efficiently catalyze the reaction. Compared with transition-metal complexes such as Ru(bpy)3Cl2 or Ir(ppy)2(dtbbpy)PF6, advantages of these surface-modified titanium dioxides as photocatalyst include high catalytic activity, low cost, ease of recovering, and being able to be used for at least nine times without significant decay of catalytic activity.
- Tang, Jian,Grampp, Günter,Liu, Yun,Wang, Bing-Xiang,Tao, Fei-Fei,Wang, Li-Jun,Liang, Xue-Zheng,Xiao, Hui-Quan,Shen, Yong-Miao
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supporting information
p. 2724 - 2732
(2015/03/18)
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- Chemical reactivity and antimicrobial activity of N-substituted maleimides
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Several N-substituted maleimides containing substituents of varying bulkiness and polarity were synthesised and tested for antimicrobial and cytostatic activity. Neutral maleimides displayed relatively strong antifungal effect minimum inhibitory concentrations (MICs in the 0.54 g ml-1 range); their antibacterial activity was structure dependent and all were highly cytostatic, with IC50 values below 0.1 g ml-1. Low antimicrobial but high cytostatic activity was noted for basic maleimides containing tertiary aminoalkyl substituents. Chemical reactivity and lipophilicity influenced antibacterial activity of neutral maleimides but had little if any effect on their antifungal and cytostatic action. N-substituted maleimides affected biosynthesis of chitin and β(1,3)glucan, components of the fungal cell wall. The membrane enzyme, β(1,3)glucan synthase has been proposed as a putative primary target of N-ethylmaleimide and some of its analogues in Candida albicans cells.
- Salewska, Natalia,Boros-Majewska, Joanna,Lcka, Izabela,Chylinska, Katarzyna,Sabisz, Michal,Milewski, Slawomir,Milewska, Maria J.
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scheme or table
p. 117 - 124
(2012/04/18)
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- Interception of an Intermediate Thiocarbonyl Ylide by NH-Compounds
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By thermal decomposition of 1,1,3,3-tetramethyl-5-thia-7,8-diazaspiro[3.4] octan2-one (1), 2,2,4,4-tetramethyl-3-thioxocyclobutanone S-methylide (2) was generated as an intermediate. This reactive "thiocarbonyl ylide" was trapped by protic agents such as alcohols, NH- and SH-acidic compounds to give 1,3-adducts of the acetal type. In a mixture of methanol and ammonia, the spiroheterocycle 1 was deprotonated and competitive ring opening of the 2,5-dihydro-1,3,4-thiadiazole and the cyclobutane ring occurred to give the hydrazono derivative 7 and the 1,3,4-thiadiazole 8, respectively. Surprisingly, 2 was intercepted by maleimide in a 1,3-dipolar cycloaddition.
- Mloston,Janicka,Woznicka,Linden,Heimgartner
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p. 1805 - 1817
(2007/10/03)
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- Process for preparation of N-substituted maleimides
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N-substituted maleimide represented by formula (2): STR1 is produced from N-substituted maleamic acid monoester represented by formula (1): STR2 in the presence of an acid catalyst by elmination of an alcohol from the monoester. The above N-substituted maleamic acid monoester represented by formula (1) is produced by esterification of N-substituted maleamic acid represented by formula (3): STR3 with an alcohol R2 -OH in the represence of an acid catalyst.
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- Syntheses of Some N-Alkylmaleimides
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An improved synthesis of N-substituted secondary and tertiary alkylmaleimides is described.
- Wang, Z. Y.
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p. 1607 - 1610
(2007/10/02)
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