56674-25-0Relevant academic research and scientific papers
Kinetics and stereochemistry of hydrolysis of an N-(phenylacetyl)-α- hydroxyglycine ester catalyzed by serine β-lactamases and dd-peptidases
Pelto, Ryan B.,Pratt
experimental part, p. 7356 - 7362 (2012/10/08)
The α-hydroxydepsipeptide 3-carboxyphenyl N-(phenylacetyl)-α- hydroxyglycinate (5) is a quite effective substrate of serine β-lactamases and low molecular mass dd-peptidases. The class C P99 and ampC β-lactamases catalyze the hydrolysis of both enantiomers of 5, although they show a strong preference for one of them. The class A TEM-2 and class D OXA-1 β-lactamases and the Streptomyces R61 and Actinomadura R39 dd-peptidases catalyze hydrolysis of only one enantiomer of 5 at any significant rate. Experiments show that all of the above enzymes strongly prefer the same enantiomer, a surprising result since β-lactamases usually prefer l(S) enantiomers and dd-peptidases d(R). Product analysis, employing peptidylglycine α-amidating lyase, showed that the preferred enantiomer is d(R). Thus, it is the β-lactamases that have switched preference rather than the dd-peptidases. Molecular modeling of the P99 β-lactamase active site suggests that the α-hydroxyl of 5 may interact with conserved Asn and Lys residues. Both α-hydroxy and α-amido substituents on a glycine ester substrate can therefore enhance its productive interaction with the β-lactamase active site, although their effects are not additive; this may also be true for inhibitors.
A comparative study of the self-immolation of para-aminobenzylalcohol and hemithioaminal-based linkers in the context of protease-sensitive fluorogenic probes
Meyer, Yves,Richard, Jean-Alexandre,Delest, Bruno,Noack, Pauline,Renard, Pierre-Yves,Romieu, Anthony
supporting information; experimental part, p. 1777 - 1780 (2010/08/20)
This study focuses on the disassembly-behavior of self-immolative pro-fluorescent linkers under physiological conditions and through an enzyme-initiated domino reaction. The targeted linkers are based on para-aminobenzylalcohol (PABA) or hemithioaminal de
One-pot, regioselective synthesis of substituted arylglycines for kinetic resolution by penicillin G acylase
Grundmann, Peter,Fessner, Wolf-Dieter
experimental part, p. 1729 - 1735 (2009/07/24)
Amido-alkylation of electron-rich arenes with phenylacetamide and glyoxylic acid offers an in-expensive route to a large variety of N-phenylacetylated arylglycines that are suited for immediate enzymatic resolution by penicillin G acylase. When performed under mild conditions at 5 °C in acetic acid/HCl, this simple one-pot operation resulted in the formation of single regioisomers only (≥98%). Subsequent kinetic resolution of the amino acid derivatives by penicillin G acylase at pH 8.0 occurred generally with E values >100 and thus furnished free (S)-configurated arylglycines with high enantiomeric purity. The corresponding enantiopure (R)-substrates, easily separable by a phase-selective extraction process, provided the corresponding (R)-enantiomers upon conventional hydrolysis. This one-pot, two-step procedure for arylglycine synthesis, resolution and work-up requires a minimum of equipment and grants rapid access to both enantiopure (S)- and (R)-antipodes of non-natural α-amino acids in small-to large-scale quantities.
Synthesis and β-lactamase reactivity of α-substituted phenaceturates
Adediran,Cabaret,Flavell,Sammons,Wakselman,Pratt
, p. 7023 - 7033 (2007/10/03)
β-Lactams with 6α (penicillins) or 7α (cephalosporins) substituents are often β-lactamase inhibitors. This paper assesses the effect of such substituents on acyclic β-lactamase substrates. Thus, a series of m-carboxyphenyl phenaceturates, substituted at the glycyl α-carbon by -OMe, -CH2OH, -CO2-, and -CH2NH3+, have been prepared, and tested for their reactivity against serine β-lactamases. The latter two are novel substituents in β-lactamase substrates. The methoxy and hydroxymethyl compounds were found to be poor to moderately good substrates, depending on the enzyme. The aminomethyl compound gave rise to a transiently stable (t1/2 = 4.6 s) complex on its reaction with a class C β-lactamase. The reactivity of the compounds against three low molecular weight dd-peptidases was also tested. Again, the methoxy and hydroxymethyl compounds proved to be quite good substrates with no sign of inhibitory complexes. The dd-peptidases reacted with one enantiomer (the compounds were prepared as racemates), presumably the d compound. The class C β-lactamase reacted with both d and l enantiomers although it preferred the latter. The structural bases of these stereo-preferences were explored by reference to the crystal structure of the enzyme by molecular modeling studies. The aminomethyl compound was unreactive with the dd-peptidases, whereas the carboxy compound did not react with any of the above-mentioned enzymes. The inhibitory effects of the -OMe and -CH2OH substituents in β-lactams apparently require a combination of the substituent and the pendant leaving group of the β-lactam at the acyl-enzyme stage.
Synthesis of pseudoxazolones and their inhibition of the 3C cysteine proteinases from hepatitis A virus and human rhinovirus-14
Ramtohul, Yeeman K.,Martin, Nathaniel I.,Silkin, Lara,James, Michael N. G.,Vederas, John C.
, p. 1351 - 1359 (2007/10/03)
The hepatitis A virus (HAV) and human rhinovirus (HRV) are important pathogens that belong to the picornavirus family. All picornaviruses have a 3C proteinase that processes an initially biosynthesised precursor protein and is crucial for viral maturation and replication. Monophenyl and diphenyl pseudoxazolones were prepared by cyclisation-elimination of N-α-chloroacyl amino acids or by condensation of p-substituted benzamides with glyoxylic acid followed by dehydrative cyclisation. Such pseudoxazolones are good time-dependent inhibitors of the HAV and HRV 3C proteinases with IC50 values in the micromolar range. Mechanistic insights into the mode of inhibition of the pseudoxazolones were obtained from mass spectrometry and gHMQC NMR spectroscopy of the HAV 3C enzyme-inhibitor complex using a pseudoxazolone labelled at the α-carbon with 13C, 13b(α-13C). The results indicate that HAV 3C proteinase was inactivated via the formation of a thioether bond by nucleophilic attack of the enzyme thiolate at the imine position of the pseudoxazolone 13b(α-13C).
