Toward the development of a cephalosporin-based dual-release prodrug for use in ADEPT

J Org Chem. 2004 Nov 12;69(23):7965-70. doi: 10.1021/jo048970i.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkylation
  • Cephalosporins / chemical synthesis*
  • Combinatorial Chemistry Techniques*
  • Molecular Structure
  • Prodrugs / chemical synthesis*
  • Stereoisomerism

Substances

  • Cephalosporins
  • Prodrugs