Synthesis and β-lactamase reactivity of α-substituted phenaceturates

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.

Figure optionsDownload as PowerPoint slide