72456-86-1Relevant academic research and scientific papers
2-Sulfonylpyridines as Tunable, Cysteine-Reactive Electrophiles
Zambaldo, Claudio,Vinogradova, Ekaterina V.,Qi, Xiaotian,Iaconelli, Jonathan,Suciu, Radu M.,Koh, Minseob,Senkane, Kristine,Chadwick, Stormi R.,Sanchez, Brittany B.,Chen, Jason S.,Chatterjee, Arnab K.,Liu, Peng,Schultz, Peter G.,Cravatt, Benjamin F.,Bollong, Michael J.
supporting information, p. 8972 - 8979 (2020/12/23)
The emerging use of covalent ligands as chemical probes and drugs would benefit from an expanded repertoire of cysteine-reactive electrophiles for efficient and diverse targeting of the proteome. Here we use the endogenous electrophile sensor of mammalian cells, the KEAP1-NRF2 pathway, to discover cysteine-reactive electrophilic fragments from a reporter-based screen for NRF2 activation. This strategy identified a series of 2-sulfonylpyridines that selectively react with biological thiols via nucleophilic aromatic substitution (SNAr). By tuning the electrophilicity and appended recognition elements, we demonstrate the potential of the 2-sulfonylpyridine reactive group with the discovery of a selective covalent modifier of adenosine deaminase (ADA). Targeting a cysteine distal to the active site, this molecule attenuates the enzymatic activity of ADA and inhibits proliferation of lymphocytic cells. This study introduces a modular and tunable SNAr-based reactive group for targeting reactive cysteines in the human proteome and illustrates the pharmacological utility of this electrophilic series.
Molecular modelling insights into a physiologically favourable approach to eicosanoid biosynthesis inhibition through novel thieno[2,3-b]pyridine derivatives
Mohamed, Mosaad S.,Mansour, Yara E.,Amin, Hatem K.,El-Araby, Moustafa E.
, p. 755 - 767 (2018/04/23)
In this research, we exploited derivatives of thieno[2,3-b]pyridine as dual inhibitors of the key enzymes in eicosanoid biosynthesis, cyclooxygenase (COX, subtypes 1 and 2) and 5-lipoxygensase (5-LOX). Testing these compounds in a rat paw oedema model revealed potency higher than ibuprofen. The most active compounds 7a, 7b, 8b, and 8c were screened against COX-1/2 and 5-LOX enzymes. Compound 7a was the most powerful inhibitor of 5-LOX with IC50 = 0.15 μM, while its p-chloro analogue 7b was more active against COX-2 (IC50 = 7.5 μM). The less desirable target COX-1 was inhibited more potently by 8c with IC50 = 7.7 μM. Surflex docking programme predicted that the more stable anti- conformer of compound (7a) formed a favourable complex with the active site of 5-LOX but not COX-1. This is in contrast to the binding mode of 8c, which resembles the syn-conformer of series 7 and binds favourably to COX-1.
Synthesis and antitumor evaluation of some new fused and binary pyridines
Waly, Mohamed A.,El-Hawary, Ibrahim I.,Hamama, Wafaa S.,Zoorob, Hanafi H.
, p. E12-E17 (2013/06/04)
Syntheses of some new heterocyclic compounds containing pyridone, thioxopyridine, halogenated-pyridine-carbonitriles, pyrazolopyridine, and pyridine derivatives were achieved. Besides, a modified synthetic method for the synthesis of 2-chloro-4,6-dimethyl-nicotinonitrile () through the reaction of acetylacetone and malononitrile as starting materials was implemented. The reaction of 2-chloronicotinonitrile with substituted amines to 2-aminonicotinonitrile were also investigated. Fused or binary pyridines were tested for cytotoxicity against well-known established model Ehrlich ascites cells in vitro. Compound exhibited a high antitumor activity compared with 5-fluorouracil.
Functional sulfur-containing compounds : 1114. Study of intramolecular cyclization of 2-organylthio-, 2-organylsulfinyl-, and 2- organylsulfonylnicotinic acid esters and nitriles upon action of a base
Kalugin,Shestopalov
experimental part, p. 2139 - 2145 (2010/04/26)
The Thorpe-Ziegler intramolecular cyclization of 2-RCH2S-, 2-RCH2S(O)-, and 2-RCH2SO2-substituted nicotinic acid esters and nitriles (R is alkyl, aryl, and 2-thienyl) upon the action of potassium tert-butoxide has been studied. The reaction results in the formation of the corresponding 2-R-substituted 3-aminothieno[2,3-b]pyridines, 3-aminothieno[2,3-b]pyridine 1-oxides, and 3-aminothieno[2,3-b]pyridine 1,1-dioxides with the reaction taking place only in the case if R is aryl or 2-thienyl. Methyl esters of 2-RCH2S-, 2-RCH2S(O)-, and 2-RCH2SO2-substituted nicotinic acids also undergo the intramolecular cyclization of the Dieckmann type to form the corresponding 2-R-substituted 3-hydroxythieno[2,3-b]pyridines, thieno[2,3-b]pyridin-3(2H)-one 1-oxides, and thieno[2,3-b]pyridin-3(2H)-one 1,1-dioxides. Such a reaction takes place for all the R groups except when R = AlkCH2S and AlkCH 2S(O).
Heteroaromatic thioether-boronic acid cross-coupling under neutral reaction conditions.
Liebeskind, Lanny S,Srogl, Jiri
, p. 979 - 981 (2007/10/03)
[reaction: see text] Pi-deficient heteroaromatic thioethers undergo efficient palladium-catalyzed cross-coupling with boronic acids mediated by copper(I) thiophene-2-carboxylate.
