Synthesis and beta-lactamase reactivity of alpha-substituted phenaceturates.
Beta-lactams with 6alpha (penicillins) or 7alpha (cephalosporins) substituents are often beta-lactamase inhibitors. This paper assesses the effect of such substituents on acyclic beta-lactamase substrates. Thus, a series of m-carboxyphenyl phenaceturates, substituted at the glycyl alpha-carbon by -OMe, -CH(2)OH, -CO(2)(-), and -CH(2)NH(3)(+), have been prepared, and tested for their reactivity against serine beta-lactamases. The latter two are novel substituents in beta-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 (t(1/2)=4.6s) complex on its reaction with a class C beta-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 beta-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 -CH(2)OH substituents in beta-lactams apparently require a combination of the substituent and the pendant leaving group of the beta-lactam at the acyl-enzyme stage.
Adediran
S A
SA
Department of Chemistry, Wesleyan University, Middletown, CT 06459, USA.
Cabaret
D
D
Flavell
R R
RR
Sammons
J A
JA
Wakselman
M
M
Pratt
R F
RF
D001665:Binding Sites; D004789:Enzyme Activation; D005998:Glycine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D006868:Hydrolysis; D008958:Models, Molecular; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013997:Time Factors; D001618:beta-Lactamases / Q000737:chemistry*
C022050:phenylacetylglycine; D001618:beta-Lactamases; D005998:Glycine