- Identification of the subtype-selective Sirt5 inhibitor balsalazide through systematic SAR analysis and rationalization via theoretical investigations
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We report here an extensive structure-activity relationship study of balsalazide, which was previously identified in a high-throughput screening as an inhibitor of Sirt5. To get a closer understanding why this compound is able to inhibit Sirt5, we initially performed docking experiments comparing the binding mode of a succinylated peptide as the natural substrate and balsalazide with Sirt5 in the presence of NAD+. Based on the evidence gathered here, we designed and synthesized 13 analogues of balsalazide, in which single functional groups were either deleted or slightly altered to investigate which of them are mandatory for high inhibitory activity. Our study confirms that balsalazide with all its given functional groups is an inhibitor of Sirt5 in the low micromolar concentration range and structural modifications presented in this study did not increase potency. While changes on the N-aroyl-β-alanine side chain eliminated potency, the introduction of a truncated salicylic acid part minimally altered potency. Calculations of the associated reaction paths showed that the inhibition potency is very likely dominated by the stability of the inhibitor-enzyme complex and not the type of inhibition (covalent vs. non-covalent). Further in-vitro characterization in a trypsin coupled assay determined that the tested inhibitors showed no competition towards NAD+ or the synthetic substrate analogue ZKsA. In addition, investigations for subtype selectivity revealed that balsalazide is a subtype-selective Sirt5 inhibitor, and our initial SAR and docking studies pave the way for further optimization.
- Bracher, Franz,Dietschreit, Johannes C. B.,Ghazy, Ehab,Glas, Carina,Jung, Manfred,Ochsenfeld, Christian,Sippl, Wolfgang,Urban, Lars,W?ssner, Nathalie
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supporting information
(2020/08/28)
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- Design, synthesis and biological evaluation of novel plumbagin derivatives as potent antitumor agents with STAT3 inhibition
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Based on the structure of signal transducer and activator of transcription 3 (STAT3), a series of 1,4-naphthoquinones derived from plumbagin (PL) with STAT3 inhibition potential were designed, synthesized, and biologically evaluated in vitro against several human cancer cell lines (MDA-MB-231, HepG2 and A549 cells) and three normal cells. The structure–activity relationship (SAR) and molecular docking result showed that the presence of hydroxyl group at C-5 of PL might interact with STAT3 in the form of hydrogen bonds, which is conducive to the binding of this kind structures with STAT3. Among the target compounds, 7a displayed the most potent inhibition against cancer cells and weaker cytotoxicity on normal cells than PL. The western bolting analysis showed that 7a could suppress the phosphorylation of STAT3 as well as the downstream genes instead of affecting its upstream tyrosine kinases (Src and JAK2) levels and p-STAT1 expression. Furthermore, molecular docking indicated that 7a bound to STAT3 more tightly than PL, and it could significantly induce the apoptosis of cancer cells in vitro. All these results may provide reference for the discovery of effective STAT3 inhibitors.
- Li, Na,Ou, Jinfeng,Bao, Na,Chen, Cheng,Shi, Zhixian,Chen, Li,Sun, Jianbo
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- Sustainable Synthesis of Balsalazide and Sulfasalazine Based on Diazotization with Low Concentrations of Nitrogen Dioxide in Air
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Low concentrations of nitrogen dioxide, which arises as a side product from a range of industrial processes, can effectively be recycled through the diazotization of anilines. The studies reported herein now demonstrate that the removal of nitrogen dioxide from gas streams is even more effective when hydrophilic anilines are used as starting materials. The diazonium salts, which are obtained in this way in up to quantitative yields, can directly be employed in azo coupling reactions, thus opening up an attractive route to the industrially important group of azo compounds.
- Hofmann, Dagmar,Gans, Eva,Krüll, Jasmin,Heinrich, Markus R.
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supporting information
p. 4042 - 4045
(2017/03/31)
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- A pharmaceutical intermediate balsalazide the nitro-benzoyl-β-alanine synthesis method (by machine translation)
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A pharmaceutical intermediate balsalazide the nitro-benzoyl-β-alanine synthesis method, comprising the following steps: in is provided with an agitator, reflux condenser, dropping funnel in the reaction container, adding sodium sulfite the 0.17 [...] 0.19mol, cyclohexanol the 0.02 [...] 0.04mol, β-alanine 0.13mol, sodium chloride solution the 90 [...] 120 ml, control the stirring speed of the 130 [...] 160rpm, nitro-benzamide dropping to the 0.13 [...] 0.16mol dissolved in 110 ml solution of methylamine is configured, the dropping time control the 3 [...] 4h, raising the temperature of the solution to 40 - - 45°C, time control of reaction in the 4 [...] 5h, separating an aqueous layer, the solution with oxalic acid, pH value of the solution is adjusted to the 4 [...] 5, separating solid, filtered, salt solution washing, dehydrating agent dehydration, the recrystallization in ethyl acetate, to obtain crystal to the nitro-benzoyl-β-alanine. (by machine translation)
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Paragraph 0013; 0014
(2016/11/14)
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- Exploration of secondary and tertiary pharmacophores in unsymmetrical N,N′-diaryl urea inhibitors of soluble epoxide hydrolase
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The impact of various secondary and tertiary pharmacophores on in vitro potency of soluble epoxide hydrolase (sEH) inhibitors based on the unsymmetrical urea scaffold 1 is discussed. N,N′-Diaryl urea inhibitors of soluble epoxide hydrolase exhibit subtle variations in inhibitory potency depending on the secondary pharmacophore but tolerate considerable structural variation in the second linker/tertiary pharmacophore fragment.
- Anandan, Sampath-Kumar,Gless, Richard D.
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scheme or table
p. 2740 - 2744
(2010/07/15)
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- Synthesis and characterization of metabolites and potential impurities of balsalazide disodium, an anti-inflammatory drug
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Balsalazide disodium (Colazide) is an oral prodrug of mesalamine (5-aminosalicylic acid) and possesses anti-inflammatory properties. During the process development for balsalazide disodium, we observed eight impurities, namely des-alanine balsalazide, balsalazide-alanine, balsalazide 3-isomer, decarboxy balsalazide, bis-azo salicylic acid, biphenyl-azo salicylic acid, bis-azo diacid, and bis-azo triacid. The present work describes the synthesis and characterization of these impurities. Copyrigh
- Khan, Md. Umar,Baseer,Kumar, S. Ranjith,Saravanakumar,Prasannanjali,Gupta, P. Badarinadh,Kaushik, Vipin K.,Handa, Vijay K.,Islam, Aminul
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scheme or table
p. 2241 - 2253
(2010/10/02)
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- Different transition-state structures for the reactions of β-lactams and analogous β-sultams with serine β-lactamases
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β-Sultams are the sulfonyl analogues of β-lactams, and N-acyl β-sultams are novel inactivators of the class C β-lactamase of Enterobacter cloacae P99. They sulfonylate the active site serine residue to form a sulfonate ester which subsequently undergoes C-O bond fission and formation of a dehydroalanine residue by elimination of the sulfonate anion as shown by electrospray ionization mass spectroscopy. The analogous N-acyl β-lactams are substrates for β-lactamase and undergo enzyme-catalyzed hydrolysis presumably by the normal acylation-deacylation process. The rates of acylation of the enzyme by the β-lactams, measured by the second-order rate constant for hydrolysis, kcat/Km, and those of sulfonylation by the β-sultams, measured by the second-order rate constant for inactivation, ki, both show a similar pH dependence to that exhibited by the β-lactamase-catalyzed hydrolysis of β-lactam antibiotics. Electron-withdrawing groups in the aryl residue of the leaving group of N-aroyl β-lactams increase the rate of alkaline hydrolysis and give a Bronsted βIg of -0.55, indicative of a late transition state for rate-limiting formation of the tetrahedral intermediate. Interestingly, the corresponding Bronsted βIg for the β-lactamase-catalyzed hydrolysis of the same substrates is -0.06, indicative of an earlier transition state for the enzyme-catalyzed reaction. By contrast, although the Bronsted βIg for the alkaline hydrolysis of N-aroyl β-sultams is -0.73, similar to that for the β-lactams, that for the sulfonylation of β-lactamase by these compounds is -1.46, compatible with significant amide anion expulsion/S-N fission in the transition state. In this case, the enzyme reaction displays a later transition state compared with hydroxide-ion-catalyzed hydrolysis of the β-sultam.
- Tsang, Wing Y.,Ahmed, Naveed,Hinchliffe, Paul S.,Wood, J. Matthew,Harding, Lindsay P.,Laws, Andrew P.,Page, Michael I.
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p. 17556 - 17564
(2007/10/03)
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- 2-Hydroxy-5-phenylazobenzoic acid derivatives and method of treating ulcerative colitis therewith
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The present invention provides a pharmaceutical composition for treating ulcerative colitis containing at least one compound of the general formula: STR1 wherein X is an --SO2 -- or --CO-- group and R is either an unsubstituted or substituted non-heterocyclic aromatic ring system or is a radical of the general formula --(CH2)n --Y, in which Y is a hydroxyl group, an unsubstituted or substituted amino group or a carboxylic or sulphonic acid group and n is a whole number of from 1 to 6 and in which one or more hydrogen atoms in the alkylene radical can be replaced by unsubstituted or substituted amino groups or alkyl radicals and in which the --(CH2)n --Y radical is either attached directly to the nitrogen atom or via a benzene ring; and/or containing at least one ester thereof and/or at least one non-toxic, pharmaceutically acceptable salt thereof, in admixture with a solid or liquid pharmaceutical diluent or carrier. Furthermore, the present invention provides a process for preparing the compounds of the above-given general formulae and also provides a method of treating ulcerative colitis.
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