Bioorganic & Medicinal Chemistry Letters 2009-02-15

Design and synthesis of a beta-lactamase activated 5-fluorouracil prodrug.

Ryan M Phelan, Marc Ostermeier, Craig A Townsend

Index: Bioorg. Med. Chem. Lett. 19(4) , 1261-3, (2009)

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Abstract

An efficient synthesis of a 5-fluorouracil-cephalosporin prodrug is described for use against colorectal and other cancers in antibody and gene-directed therapies. The compound shows stability in aqueous media until specifically activated by beta-lactamase (betaL). The kinetic parameters of the 5-fluorouracil-cephalosporin conjugate were determined in the presence of Enterobacter cloacae P99 betaL (ECl betaL) revealing a K(m)=95.4 microM and V(max)=3.21 microMol min(-1) mg(-1). The data compare favorably to related systems that have been reported and enable testing of this prodrug against cancer cell lines in vitro and in vivo.