New stereoselective reaction of methylglyoxal with 2-aminopyridine and adenine derivatives: Formation of imino acid-nucleic base derivatives in water under mild conditions

Routaboul, C.; Dumas, L.; Gautier‐Luneau, Isabelle; Vergne, Jacques; Maurel, Marie‐Christine; Décout, Jean‐Luc

doi:10.1039/b201901a

Cited by 14 publications

(17 citation statements)

References 18 publications

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“…The enantiomers 2a and their isomers 2b obtained from 2-aminopyridine and the corresponding adenine adducts 4a have been characterized by X-ray crystallography ( Fig. 2) (Routaboul et al, 2002). After the reaction and removal of methylglyoxal in excess, the isomers a and b could be detected by NMR spectrometry in a ratio of 60:40.…”

Section: Resultsmentioning

confidence: 99%

“…2). Both diastereomers a and b could be detected by NMR spectrometry but could not be separated (Routaboul et al, 2002). To modulate the lipophily of the adducts, new methylglyoxal adducts 3a,b, 7a,b, and 8a,b were prepared.…”

Section: Resultsmentioning

confidence: 99%

“…Previously, we had reported a new reaction between methylglyoxal 1 and an aromatic ␣-aminoazaheterocycle such as 2-aminopyridine or adenine, leading in water to heterocycles of a new class (Routaboul et al, 2002). Condensation in water of two molecules of methylglyoxal on the heterocycle results in the formation in good yields of a new six-membered ring carrying a carboxylate function, two hydroxyl and two methyl groups (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Pyruvic aldehyde (methylglyoxal) aqueous solution (40%), adenine, adenosine, 1-aminoisoquinoline, 2-amino-3-hydroxypyridine, 2-aminopyridine and 2Ј-deoxyadenosine were purchased from Sigma-Aldrich (St. Louis, MO). The synthesis and characterization of compounds 2, 4, 5, and 6 have been described previously (Routaboul et al, 2002).…”

Section: Methodsmentioning

confidence: 99%

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Discovery of α-Aminoazaheterocycle-Methylglyoxal Adducts as a New Class of High-Affinity Inhibitors of Cystic Fibrosis Transmembrane Conductance Regulator Chloride Channels

Routaboul

Norez²,

Melin³

et al. 2007

J Pharmacol Exp Ther

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The cystic fibrosis transmembrane conductance regulator (CFTR) represents the main Cl Ϫ channel in the apical membrane of epithelial cells for cAMP-dependent Cl Ϫ secretion. Here we report on the synthesis and screening of a small library of nontoxic ␣-aminoazaheterocycle-methylglyoxal adducts, inhibitors of wild-type (WT) CFTR and G551D-, G1349D-, and F508del-CFTR Cl Ϫ channels. In whole-cell patch-clamp experiments of Chinese hamster ovary (CHO) cells expressing WT-CFTR, we recorded rapid and reversible inhibition of forskolin-activated CFTR currents in the presence of the adducts 5a and 8a,b at 10 pM concentrations. Using iodide efflux experiments, we compared concentration-dependent inhibition of CFTR with glibenclamide (IC 50 ϭ 14.7 M), 3-[(3-trifluoromethyl)phenyl]-5-[(4-carboxyphenyl-)methylene]-2-thioxo-4-thiazolidinone (CFTR inh -172) (IC 50 ϭ 1.2 M), and ␣-aminoazaheterocycle-methylglyoxal adducts and identified compounds 5a (IC 50 ϭ 71 pM), 8a,b (IC 50 ϭ

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Discovery of α-Aminoazaheterocycle-Methylglyoxal Adducts as a New Class of High-Affinity Inhibitors of Cystic Fibrosis Transmembrane Conductance Regulator Chloride Channels

Routaboul

Norez²,

Melin³

et al. 2007

J Pharmacol Exp Ther

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“…1a) is a very potent CFTR inhibitor [13,14]. Here, following a structure-activity study, we identified methylglyoxal-9-propyladenine adducts ( fig.…”

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confidence: 99%

Identification of a novel water-soluble activator of wild-type and F508del CFTR: GPact-11a

Bertrand¹,

Boucherle²,

Billet³

et al. 2010

European Respiratory Journal

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One of the major therapeutic strategy in cystic fibrosis aims at developing modulators of cystic fibrosis transmembrane conductance regulator (CFTR) channels. We recently discovered methylglyoxal a-aminoazaheterocycle adducts, as a new family of CFTR inhibitors. In a structure-activity relationship study, we have now identified GPact-11a, a compound able not to inhibit but to activate CFTR.Here, we present the effect of GPact-11a on CFTR activity using in vitro (iodide efflux, fluorescence imaging and patch-clamp recordings), ex vivo (short-circuit current measurements) and in vivo (salivary secretion) experiments.We report that GPact-11a: 1) is an activator of CFTR in several airway epithelial cell lines; 2) activates rescued F508del-CFTR in nasal, tracheal, bronchial, pancreatic cell lines and in human CF ciliated epithelial cells, freshly dissociated from lung samples; 3) stimulates ex vivo the colonic chloride secretion and increases in vivo the salivary secretion in cftr +/+ but not cftr -/-mice; and 4) is selective for CFTR because its effect is inhibited by CFTR inh -172, GlyH-101, glibenclamide and GPinh-5a. To conclude, this work identifies a selective activator of wild-type and rescued F508del-CFTR. This nontoxic and water-soluble agent represents a good candidate, alone or in combination with a F508del-CFTR corrector, for the development of a CFTR modulator in cystic fibrosis.

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