Exploring the chemistry of penicillin as a beta-lactamase-dependent prodrug.

The penam nucleus can be modified to behave as a beta-lactamase-dependent 'prodrug' by incorporation of a vinyl ester side chain at the 6-position. Enzyme-catalysed hydrolysis of the beta-lactam ring uncovers the thiazolidine-ring nitrogen as a nucleophile that drives a rapid intramolecular displacement on the side chain. Attachment of 7-hydroxy-4-methylcoumarin as the releasable group of this side chain generated a penicillin structure that can function as a fluorescence-based reporter substance/diagnostic for the presence of low levels of beta-lactamase enzyme in solution. Mechanistic details of the reaction pattern are documented and the scope and limitations of exploiting the structural modification are discussed.

Penicillins as beta-lactamase-dependent prodrugs: enabling role of a vinyl ester exocyclic to the lactam ring.

Incorporation of a vinyl ester exocyclic to the beta-lactam ring of a penicillin nucleus enables this to act as a beta-lactamase-dependent prodrug - rapid release of the (unactivated) alkoxy component of the vinyl ester is triggered by enzyme-catalysed hydrolysis of the beta-lactam ring, whilst buffer-catalysed hydrolysis of the structure at neutral pH is particularly slow.