Design and synthesis of a beta-lactamase activated 5-fluorouracil prodrug.
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.
Phelan
Ryan M
RM
Department of Chemistry, Johns Hopkins University, 3400 N. Charles St., Baltimore, MD 21212, USA.
Ostermeier
Marc
M
Townsend
Craig A
CA
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002511:Cephalosporins / Q000138:chemical synthesis / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D016972:Enterobacter cloacae / Q000201:enzymology*; D005472:Fluorouracil / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001618:beta-Lactamases / Q000276:immunology / Q000378:metabolism*
D000970:Antineoplastic Agents; D002511:Cephalosporins; D011355:Prodrugs; D001618:beta-Lactamases; D005472:Fluorouracil