Toward the Development of a Cephalosporin-Based Dual-Release Prodrug for Use in ADEPT

Abstract

In previous work we have shown that a cephalosporin structure bearing an S-aminosulfenimine at the 7-position behaved as a beta-lactamase-dependent dual-release prodrug. Scission of the beta-lactam ring of such a structure led to the rapid loss of the sulfur-attached side chain moiety via an intramolecular displacement, while the 3'-group was lost via the well-established elimination process at that position. In the present work we report on an evaluation of the scope and limitations of exploiting the S-aminosulfenimine functionality to generate a cephalosporin-based prodrug incorporating two biologically active components. Starting from 7-ACA, a viable synthetic cycle was put in place that avoided formation of the Delta(2) isomer throughout and that allowed incorporation of aminoglutethimide at the 3'-position and of a tosyl S-aminosulfenimine at the 7-position. The direct incorporation of a biologically active sulfonamide (ethoxzolamide) or a sulfamate (coumate) at this latter position was not achieved as a result of the difficulty of generating the corresponding sulfur diimides. An indirect route for the formation of an S-aminosulfenimine was put in place, as was a general method of alkylation (Mitsunobu reaction) of the tosyl S-aminosulfenimine following its incorporation.

Enzymatic Deprotection of the Cephalosporin 3′-Acetoxy Group Using Candida antarctica Lipase B

“…Enzymatic deprotection of the cephalosporin acetoxy group has been demonstrated in the literature . Similar to chemical deacetylations, the enzymatic deacetylation reactions have only been reported when the cephalosporin contains a free acid .…”

Dual Action-Based Approaches to Antibacterial Agents

“…Unfortunately the true potential of these dual release prodrugs have not been realized from a designed antibacterial viewpoint, as all Smyth's compounds [32] incorporated leaving groups resulting in simple alcohols. However, extension of this work to antibodydirected enzyme prodrug therapy for the selective release of both coumate and R-(+)-aminoglutethimide as sulfatase and aromatase inhibitors respectively for the reduction of estrogen hormone-dependent breast cancer has been reported [33].…”

Engineering of Cysteine Residues Leads to Improved Production of a Human Dipeptidase Enzyme in E. coli

“…MDP is the only human β-lactamase known to date and hydrolyses both penem and carbapenem β-lactam antibiotics [21]. This has led to β-lactam ring-containing molecules with structural similarity to MDP's natural substrates being used as prodrug nuclei in ADEPT (antibody-directed enzyme prodrug therapy) cancer chemotherapy [22,23].…”