Extending the β-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 β-lactamase-dependent prodrug. Enzyme-catalyzed hydrolysis of the β-lactam ring in these structures triggers release of both the 3‘-acetoxy group and the side chain su...

Full description

Saved in:
Bibliographic Details
Published in:Journal of organic chemistry 1999-04, Vol.64 (9), p.3132-3138
Main Authors: Smyth, Timothy P, O'Conno, Michael J, O'Donnell, Michael E
Format: Article
Language:English
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Cephalosporins bearing an S-aminosulfenimine (R‘(R‘ ‘)NSN) side chain at the 7-position are prototypic examples of a novel class of β-lactamase-dependent prodrug. Enzyme-catalyzed hydrolysis of the β-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 β-lactamase-based resistance to antibiotics.
ISSN:0022-3263
1520-6904
DOI:10.1021/jo981993a