A protocol for amide bond formation with electron deficient amines and sterically hindered substrates

Due-Hansen, Maria E.; Pandey, Sunil; Christiansen, Elisabeth; Andersen, Rikke; Hansen, Steffen V. F.; Ulven, Trond

doi:10.1039/c5ob02129d

Cited by 83 publications

(56 citation statements)

References 29 publications

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“…The reactions with N‐( 3‐dimethylaminopropyl)‐ N ′‐ethylcarbodiimide hydrochloride (EDC), N , N , N′ , N′ ‐tetramethyl‐ O ‐(1 H ‐benzotriazol‐1‐yl)uronium hexafluorophosphate (HBTU), and N ‐ethoxycarbonyl‐2‐ethoxy‐1,2‐dihydroquinoline (EEDQ) as coupling agents failed to improve the reaction output . Finally, we decided to adopt the procedure of Ulven and co‐workers; the use of chlorodipyrrolidinocarbenium hexafluorophosphate (PyClU) as the coupling reagent allowed us to isolate CoumDimer . The first reaction was performed in ethylene chloride, but the yield was not satisfactory (21 %).…”

Section: Resultsmentioning

confidence: 99%

The Coumarin‐Dimer Spring—The Struggle between Charge Transfer and Steric Interactions

Kielesiński

Morawski

Sobolewski

et al. 2017

Chemistry A European J

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The synthesis of a weakly coupled, strongly polarized coumarin dimer has been achieved for the first time. The three-step strategy comprises the Skattebøl formylation followed by the Knoevenagel reaction and the formation of a tertiary amide by using a peptide-type procedure. The molecule consists of two different coumarin moieties: One is a classical donor-acceptor system and the second one possesses a weaker amide donor at the 7-position. The polarized coumarin dimer can form an electronically conjugated structure possessing an electric dipole larger than that of 7-(dimethylamino)coumarin-3-carboxylic acid. The limited flexibility of the inter-coumarin connection results in stable conformers of different electric dipole moments and complex photophysics. In the solid state, this compound has a strongly bent conformation with the two coumarin units forming an angle of around 74°. In solution, two conformers are in equilibrium. The existence of the molecule as two conformers in the ground state has been confirmed by optical studies, and further corroborated by molecular calculations. The fluorescence spectra possess a unique feature: A charge-transfer band (ca. 550 nm) is visible only in nonpolar or weakly polar solvents. Optical spectroscopy studies coupled with molecular calculations allowed us to rationalize this phenomenon: The large amplitude of intramolecular motions is responsible for the conformational isomerization as well as producing a conical intersection between the potential energy surfaces of the excited singlet state and the ground state, which opens an internal conversion channel that effectively competes with the fluorescence of the conformers.

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Section: Resultsmentioning

confidence: 99%

The Coumarin‐Dimer Spring—The Struggle between Charge Transfer and Steric Interactions

Kielesiński

Morawski

Sobolewski

et al. 2017

Chemistry A European J

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“…The allosteric FFA2R modulator AZ1729 (Bolognini et al, 2016) was a generous gift from AstraZeneca (Mölndal, Sweden) and the phenylacetamide compound (S)-2-(4-chlorophenyl)-3,3-dimethyl-N-(5-phenylthiazol-2-yl)butanamide (PA;Cmp58 (Wang et al, 2010)) was obtained from Calbiochem-Merck Millipore (Billerica, USA) The Gαq inhibitor YM-254890 was purchased from Wako Chemicals (Neuss, Germany). The FFA2R antagonist CATPB ((S)-3-(2-(3-chlorophenyl)acetamido)-4-(4-(trifluoromethyl)-phenyl) butanoic acid) synthesized as described previously (Due-Hansen et al, 2015; Hudson et al, 2013; Hudson et al, 2012), was a generous gift from Trond Ulven (Odense university, Denmark). The P2Y 2 R antagonist AR-C118925XX (5-[[5-(2,8-Dimethyl-5 H -dibenzo[ a , d ]cyclohepten-5-yl)-3,4-dihydro-2-oxo-4-thioxo-1(2 H )-pyrimidinyl]methyl]- N -2 H -tetrazol-5-yl-2-furancarboxamide) was obtained from Tocris (Abingdon, UK).…”

Section: Methodsmentioning

confidence: 99%

Interdependent Allosteric FFA2R Modulators Synergistically Induce Functional Selective Activation and Desensitization in Neutrophils

Lind

Holdfeldt

Mårtensson

et al. 2019

Preprint

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The non-activating allosteric modulator AZ1729, specific for free fatty acid receptor 2 (FFA2R), transfers the orthosteric FFA2R agonists propionate and the P2Y2R specific agonist ATP into activating ligands that trigger an assembly of the neutrophil superoxide generating NADPH-oxidase. The homologous priming effect on the propionate response and the heterologous receptor cross-talk sensitized ATP response mediated by AZ1729 are functional characteristics shared with Cmp58, another non-activating allosteric FFA2R modulator. In addition, AZ1729 also turned Cmp58 into a potent activator of the superoxide generating neutrophil NADPH-oxidase, and in agreement with the allosteric modulation concept, the effect was reciprocal in that Cmp58 turned AZ1729 into a potent activating allosteric agonist. The activation signals down-stream of FFA2R when stimulated by the two interdependent allosteric modulators were biased in that, unlike for orthosteric agonists, the two complementary modulators together triggered an activation of the NADPH-oxidase, but not any transient rise in the cytosolic concentration of free Ca2+. In addition, following AZ1729/Cmp58 activation, signaling by the desensitized FFA2Rs was functionally selective in that the orthosteric agonist propionate could still induce a transient rise in intracellular Ca2+. The novel neutrophil activation and receptor down-stream signaling pattern mediated by the two cross-sensitizing allosteric FFA2R modulators represents a new regulatory mechanism that controls receptor signaling.Significance StatementA novel activation mechanism of a G-protein coupled free fatty acid receptor (FFA2R), is synergistically triggered by two otherwise non-activating allosteric modulators in the absence of orthosteric agonists. The receptor down-stream signaling proved to be functionally selective (biased); a superoxide generating enzyme is assembled and activated without involvement of the Ca2+ signaling pathway. The novel activation mechanism and the receptor down-stream signaling pattern mediated by the two cross-sensitizing allosteric FFA2R modulators, represents a new regulatory mechanism for control of GPCR-signaling.

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“…Compound 1 was synthesized as described previously (54). 4-CMTB was synthesized as described previously (18).…”

Section: Methodsmentioning

confidence: 99%

A Novel Allosteric Activator of Free Fatty Acid 2 Receptor Displays Unique Gi-functional Bias

Bolognini

Moss

Nilsson

et al. 2016

Journal of Biological Chemistry

104

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The short chain fatty acid receptor FFA2 is able to stimulate signaling via both Gi- and Gq/G11-promoted pathways. These pathways are believed to control distinct physiological end points but FFA2 receptor ligands appropriate to test this hypothesis have been lacking. Herein, we characterize AZ1729, a novel FFA2 regulator that acts as a direct allosteric agonist and as a positive allosteric modulator, increasing the activity of the endogenously produced short chain fatty acid propionate in Gi-mediated pathways, but not at those transduced by Gq/G11. Using AZ1729 in combination with direct inhibitors of Gi and Gq/G11 family G proteins demonstrated that although both arms contribute to propionate-mediated regulation of phospho-ERK1/2 MAP kinase signaling in FFA2-expressing 293 cells, the Gq/G11-mediated pathway is predominant. We extend these studies by employing AZ1729 to dissect physiological FFA2 signaling pathways. The capacity of AZ1729 to act at FFA2 receptors to inhibit β-adrenoreceptor agonist-promoted lipolysis in primary mouse adipocytes and to promote chemotaxis of isolated human neutrophils confirmed these as FFA2 processes mediated by Gi signaling, whereas, in concert with blockade by the Gq/G11 inhibitor FR900359, the inability of AZ1729 to mimic or regulate propionate-mediated release of GLP-1 from mouse colonic preparations defined this physiological response as an end point transduced via activation of Gq/G11.

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A protocol for amide bond formation with electron deficient amines and sterically hindered substrates

Abstract: A protocol for amide coupling by in situ formation of acyl fluorides and reaction with amines at elevated temperature has been developed and found to be efficient for coupling of sterically hindered substrates and electron deficient amines where standard methods failed.

Cited by 83 publications

References 29 publications

The Coumarin‐Dimer Spring—The Struggle between Charge Transfer and Steric Interactions

The Coumarin‐Dimer Spring—The Struggle between Charge Transfer and Steric Interactions

Interdependent Allosteric FFA2R Modulators Synergistically Induce Functional Selective Activation and Desensitization in Neutrophils

A Novel Allosteric Activator of Free Fatty Acid 2 Receptor Displays Unique Gi-functional Bias

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