title: Extending the beta-Lactamase-Dependent Prodrug Armory: S-Aminosulfeniminocephalosporins as Dual-Release Prodrugs.
abstract: 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.
authors.affiliation: Department of Chemical and Environmental Sciences, University of Limerick, National Technological Park, County Limerick, Ireland.
authors.forename: Timothy P.
authors.initials: TP
authors.lastname: Smyth
authors.forename: Michael J.
authors.initials: MJ
authors.lastname: O'Connor
authors.forename: Michael E.
authors.initials: ME
authors.lastname: O'Donnell