1197-51-9Relevant articles and documents
Synthesis of multiply substituted 1,6-dihydropyridines through Cu(I)-catalyzed 6-endo cyclization
Mizoguchi, Haruki,Watanabe, Ryo,Minami, Shintaro,Oikawa, Hideaki,Oguri, Hiroki
, p. 5955 - 5963 (2015)
Copper-catalyzed 6-endo cyclization of N-propargylic β-enaminocarbonyls was developed for the synthesis of oxidation-labile 1,6-dihydropyridines. This synthetic method allows flexible and regio-defined assembly of various substituents at the N1, C2, C3, C4, and C6 positions of 1,6-dihydropyridines under mild conditions.
Synthesis and structure-activity studies of novel anhydrohexitol-based Leucyl-tRNA synthetase inhibitors
De Ruysscher, Dries,Pang, Luping,Lenders, Stijn M.G.,Cappoen, Davie,Cos, Paul,Rozenski, Jef,Strelkov, Sergei V.,Weeks, Stephen D.,Van Aerschot, Arthur
, (2021)
Leucyl-tRNA synthetase (LeuRS) is a clinically validated target for the development of antimicrobials. This enzyme catalyzes the formation of charged tRNALeu molecules, an essential substrate for protein translation. In the first step of catalysis LeuRS activates leucine using ATP, forming a leucyl-adenylate intermediate. Bi-substrate inhibitors that mimic this chemically labile phosphoanhydride-linked nucleoside have proven to be potent inhibitors of different members of the aminoacyl-tRNA synthetase family but, to date, they have demonstrated poor antibacterial activity. We synthesized a small series of 1,5-anhydrohexitol-based analogues coupled to a variety of triazoles and performed detailed structure-activity relationship studies with bacterial LeuRS. In an in vitro assay, Kiapp values in the nanomolar range were demonstrated. Inhibitory activity differences between the compounds revealed that the polarity and size of the triazole substituents affect binding. X-ray crystallographic studies of N. gonorrhoeae LeuRS in complex with all the inhibitors highlighted the crucial interactions defining their relative enzyme inhibitory activities. We further examined their in vitro antimicrobial properties by screening against several bacterial and yeast strains. While only weak antibacterial activity against M. tuberculosis was detected, the extensive structural data which were obtained could make these LeuRS inhibitors a suitable starting point towards further antibiotic development.
Functionalized triazolopeptoids-a novel class for mitochondrial targeted delivery
Althuon, Daniela,R?nicke, Franziska,Fürniss, Daniel,Quan, Jasmin,Wellh?fer, Isabelle,Jung, Nicole,Schepers, Ute,Br?se, Stefan
, p. 4226 - 4230 (2015)
Here we introduce linear 1,4-triazolopeptoids as a novel class of cell penetrating peptidomimetics suitable as organ targeting molecular transporters of bioactive cargo. Repetitive triazole moieties with up to three residues were assembled on solid supports using copper-catalyzed alkyne-azide cycloadditions (CuAAC) in a submonomer approach. Depending on the lipophilicity of their side chain appendages the 1,4-triazolopeptoids showed either endosomal localization or a strong colocalization with the mitochondria of HeLa cells with moderate toxicity. While the basic triazolopeptoids mainly target the neuromast cells in zebrafish embryos, the lipophilic ones colocalize with either cartilage in the jaws and the blood vessel system. This journal is
The regiochemistry of carbenoid insertion into zirconacycles
Gordon, George J.,Luker, Tim,Tuckett, Mark W.,Whitby, Richard J.
, p. 2113 - 2129 (2000)
The regioselectivity of insertion of lithium chloroallylides (allyl carbenoids) into a wide variety of unsymmetrical zirconacycles has been determined. In all but one case a single regioisomer was obtained. A combination of steric and electronic effects is needed to explain the results and imply that the carbenoid is acting predominantly as an electrophilic species. The first carbenoid insertion into a zirconacyclopentadiene is noted. (C) 2000 Elsevier Science Ltd.
Robust Silver(I) Catalyst for the Carboxylative Cyclization of Propargylic Alcohols with Carbon Dioxide under Ambient Conditions
Song, Qing-Wen,He, Liang-Nian
, p. 1251 - 1258 (2016)
Inspired by the bulkier bis(triphenylphosphine)-silver cation-induced mechanism of propargylic alcohols and carbon dioxide through the alkyl carbonate intermediate, a robust dual-component catalytic system consisting of silver acetate and tetraheptylammonium bromide was rationally developed for the synthesis of α-methylene cyclic carbonates under ambient conditions without employing any additional organic base and ligand. This is one of the most effective catalysts reported to date for this conversion, with a very high turnover number of up to 6024, probably due to the synergistic effect of Lewis basic and Lewis acidic species for the activation of both propargylic alcohol and carbon dioxide by the formation of the alkyl carbonate with a bulkier counterion. Notably, this catalyst also worked well for the carboxylative cyclization of propargylic amines with carbon dioxide with the highest turnover number of 544.
Highly regioselective synthesis of substituted isoindolinones via ruthenium-catalyzed alkyne cyclotrimerizations
Foster, Robert W.,Tame, Christopher J.,Hailes, Helen C.,Sheppard, Tom D.
, p. 2353 - 2360 (2013)
(Cyclooctadiene)(pentamethylcyclopentadiene) ruthenium chloride [Cp*RuCl (cod)] has been used to catalyze the regioselective cyclization of amide-tethered diynes with monosubstituted alkynes to give polysubstituted isoindolinones. Notably, the presence of a trimethylsilyl group on the diyne generally led to complete control over the regioselectivity of the alkyne cyclotrimerization. The cyclization reaction worked well in a sustainable non-chlorinated solvent and was tolerant of moisture. The optimized conditions were effective with a diverse range of alkynes and diynes. The 7-silylisoindolinone products could be halogenated, protodesilylated or ring opened to access a range of usefully functionalized products.
Novel glucopyranoside C2-derived 1,2,3-triazoles displaying selective inhibition of O-GlcNAcase (OGA)
Igual, Michelle O.,Nunes, Paulo S.G.,da Costa, Rafael M.,Mantoani, Susimaire P.,Tostes, Rita C.,Carvalho, Ivone
, p. 43 - 55 (2019)
O-GlcNAcylation or O-GlcNAc modification is a post-translational modification of several proteins responsible for fundamental cellular processes. Dysregulation of the O-GlcNAc pathway has been linked to the etiology of several diseases such as neurodegenerative and cardiovascular diseases, type 2 diabetes and cancer. O-GlcNAcase (OGA) catalyzes the removal of O-GlcNAc from the modified proteins and several carbohydrate-based OGA inhibitors have been synthesized to understand the role of O-GlcNAc-modified proteins in physiological and pathological conditions. However, many of the inhibitors lack selectivity for OGA over lysosomal hexosaminidases A and B. Aiming the selectively inhibition of OGA, we propose herein the synthesis of twelve novel glucopyranoside derivatives exploring the bioisosteric replacement of the GlcNAc 2-acetamide group by 1,4-disubstituted 1,2,3-triazole ring, bearing a variety of central chains with different shapes. Compounds were readily prepared through “Copper(I) Catalyzed Azide/Alkyne Cycloaddition” (CuAAC) reaction between a sugar azide and different terminal alkynes. Initial Western Blot analyses and further inhibitory assays proved that compounds 6a (IC50 = 0.50 ± 0.02 μM, OGA), 6k (IC50 = 0.52 ± 0.01 μM, OGA) and 6l (IC50 = 0.72 ± 0.02 μM, OGA) were the most potent and selective compounds of the series. Structure-activity relationship analyses and molecular docking simulations demonstrated that the bridge of two-carbon atoms between the C-4 position of the triazole and the phenyl ring (6a), which may be replaced by heteroatoms such as N (6k) or O (6l), is fundamental for accommodation and inhibition within OGA catalytic pocket.
Synthesis of polysubstituted pyrroles from activated alkynes and n-propargylamines through base-catalyzed cascade reaction
Weng, Jianquan,Chen, Yong,Yue, Binjie,Xu, Meng,Jin, Hongwei
, p. 3164 - 3170 (2015)
A novel K3PO4-catalyzed synthesis of polysubstituted pyrroles by a Michael addition/alkyne carbocyclization of activated alkynes and N-propargylamines has been developed. This transition-metal-free cascade process represents an environmental friendly and efficient way to construct polysubstituted pyrroles in good yields. Catalyzed by CsF, a Michael addition/aza-Claisen rearrangement/cyclization sequential process has been achieved to selectively synthesize pyrroles in moderate yields. An efficient method for the synthesis of polysubstituted pyrroles from activated alkynes and N-propargylamines has been developed. This cascade process represents an atom- and step-economical way to construct a range of polysubstituted pyrroles and involves base-catalyzed Michael addition/alkyne carbocyclization or Michael addition/aza-Claisen rearrangement/cyclization.
N-Cyanation of Primary and Secondary Amines with Cyanobenzio-doxolone (CBX) Reagent
Chen, Zimin,Yuan, Weiming
supporting information, p. 14836 - 14840 (2021/09/30)
An efficient electrophilic N-cyanation of amines with a stable and less-toxic cyanobenziodoxole reagent towards the synthesis of cyanamides is disclosed. This synthetically practicable strategy allows the construction of a wide variety of cyanamides under very mild and simple conditions with a broad functional group compatibility, and showcases a huge potential in late-stage modification of complex molecules.
N-Propargylamine-hydroxypyridinone hybrids as multitarget agents for the treatment of Alzheimer's disease
Bai, Renren,Ge, Jiamin,Guo, Jianan,Jiang, Xiaoying,Xie, Yuanyuan,Yao, Chuansheng,Zhang, Changjun,Zhang, Jingqi,Zhang, Yujia,Zhong, Zhichao,Zhou, Tao
, (2021/06/07)
AD is a progressive brain disorder. Because of the lack of remarkable single-target drugs against neurodegenerative disorders, the multitarget-directed ligand strategy has received attention as a promising therapeutic approach. Herein, we rationally designed twenty-nine hybrids of N-propargylamine-hydroxypyridinone. The designed hybrids possessed excellent iron-chelating activity (pFe3+ = 17.09–22.02) and potent monoamine oxidase B inhibitory effects. Various biological evaluations of the optimal compound 6b were performed step by step, including inhibition screening of monoamine oxidase (hMAO-B IC50 = 0.083 ± 0.001 μM, hMAO-A IC50 = 6.11 ± 0.08 μM; SI = 73.5), prediction of blood–brain barrier permeability and mouse behavioral research. All of these favorable results proved that the N-propargylamine-hydroxypyridinone scaffold is a promising structure for the discovery of multitargeted ligands for AD therapy.
