Extending the beta-Lactamase-Dependent Prodrug Armory: S-Aminosulfeniminocephalosporins as Dual-Release Prodrugs.
Cephalosporins bearing an S-aminosulfenimine (R'(R' ')NSN=) side chain at the 7-position are prototypic examples of a novel class of beta-lactamase-dependent prodrug. Enzyme-catalyzed hydrolysis of the beta-lactam ring in these structures triggers release of both the 3'-acetoxy group and the side chain sulfur-attached S-amino moiety as R'(R' ')NH. This reactivity pattern should allow site-specific corelease of two distinct drug components from a cephalosporin, thereby providing a singular enhancement to the capacity of a cephalosporin as a prodrug nucleus; a key advantage of a dual-release prodrug is the potential to establish synergy between the coreleased structures. Areas for exploitation of this new structure type are antibody-directed enzyme prodrug therapy (ADEPT), which is a key emerging anticancer therapy, and the further development of site-specific-release prodrugs to combat the problem of beta-lactamase-based resistance to antibiotics.
Smyth
Timothy P.
TP
Department of Chemical and Environmental Sciences, University of Limerick, National Technological Park, County Limerick, Ireland.
O'Connor
Michael J.
MJ
O'Donnell
Michael E.
ME