- Identification of the subtype-selective Sirt5 inhibitor balsalazide through systematic SAR analysis and rationalization via theoretical investigations
-
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
-
-
- A synthetic balsalazide sodium intermediates (by machine translation)
-
A synthetic balsalazide sodium intermediates, which belongs to the technical field of pharmaceutical intermediates. The process in the nitro also reduced to ammonia for use by a Zr12 - TPDC - Pd as a catalyst, the catalyst for the water directly as solvent, at room temperature under atmospheric pressure of hydrogen atmosphere can be the step of the reaction yield is improved to 99% or more. In the direct reaction of the water, the separation of the intermediate product is not used, the production process is greatly simplified, at the same time reduce organic solvent to the environment caused by pollution, the final product is that the product is a yellow or red yellow crystalline powder; odorless; bitter taste, purity is very high. Using efficient Zr12 - TPDC - Pd catalyst reduces the environment pollution and difficulty of post-processing; and easy operation, processing is simple. By adopting the optimized synthetic route, has greatly improved yield, reduce the cost, improve the safety, energy saving and the like, in accordance with the green reaction of modern chemical production requirement. (by machine translation)
- -
-
Paragraph 0012
(2019/01/07)
-
- Sustainable Synthesis of Balsalazide and Sulfasalazine Based on Diazotization with Low Concentrations of Nitrogen Dioxide in Air
-
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.
-
p. 4042 - 4045
(2017/03/31)
-
- Synthesis and characterization of metabolites and potential impurities of balsalazide disodium, an anti-inflammatory drug
-
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
-
experimental part
p. 2241 - 2253
(2010/10/02)
-
- Exploration of secondary and tertiary pharmacophores in unsymmetrical N,N′-diaryl urea inhibitors of soluble epoxide hydrolase
-
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.
-
scheme or table
p. 2740 - 2744
(2010/07/15)
-
- 2-Hydroxy-5-phenylazobenzoic acid derivatives and method of treating ulcerative colitis therewith
-
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.
- -
-
-
