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Novel fluorinated prodrugs for activation by carboxypeptidase G2 showing good in vivo antitumor activity in gene-directed enzyme prodrug therapy.

Abstract
Sixteen novel polyfluorinated benzoic acid mustards have been synthesized for use in gene-directed enzyme prodrug therapy (GDEPT). Eight of these were benzoic acid L-glutamate mustards for evaluation as prodrugs and the other eight were the active drugs formed by the action of the bacterial enzyme carboxypeptidase G2 (CPG2). All of the di- and trifluorinated prodrugs were efficiently cleaved by the enzyme. In contrast, the tetrafluorinated prodrugs were found to be competitive inhibitors of CPG2, the first such inhibitors to have been described. The di- and trifluorinated prodrugs were differentially cytotoxic to human breast carcinoma cells (MDA MB 361) expressing CPG2, compared to control cells that did not express the enzyme. The difluorinated prodrug {4-[bis(2-bromoethyl)amino]-3,5-difluorobenzoyl}-L-glutamic acid and its iodoethylamino analogue were effective substrates for the enzyme and showed excellent therapeutic activity in CPG2-expressing MDA MB 361 xenografts, either curing or greatly inhibiting tumor growth and extending the life of the animals.
AuthorsLawrence C Davies, Frank Friedlos, Douglas Hedley, Jan Martin, Lesley M Ogilvie, Ian J Scanlon, Caroline J Springer
JournalJournal of medicinal chemistry (J Med Chem) Vol. 48 Issue 16 Pg. 5321-8 (Aug 11 2005) ISSN: 0022-2623 [Print] United States
PMID16078849 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Mustard Compounds
  • Prodrugs
  • Fluorine
  • gamma-Glutamyl Hydrolase
Topics
  • Animals
  • Antineoplastic Agents (chemical synthesis, chemistry, metabolism, pharmacology)
  • Breast Neoplasms
  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor
  • Female
  • Fluorine
  • Humans
  • Mice
  • Mice, Nude
  • Mustard Compounds (chemical synthesis, chemistry, metabolism, pharmacology)
  • Neoplasm Transplantation
  • Prodrugs (chemical synthesis, chemistry, metabolism, pharmacology)
  • Structure-Activity Relationship
  • Transplantation, Heterologous
  • gamma-Glutamyl Hydrolase (genetics, metabolism)

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