Novel Fluorinated Prodrugs for Activation by Carboxypeptidase G2 Showing Good in Vivo Antitumor Activity in Gene-Directed Enzyme Prodrug Therapy

• Published in: Journal of medicinal chemistry 2005-08, Vol.48 (16), p.5321-5328
• Main Authors: Davies, Lawrence C, Friedlos, Frank, Hedley, Douglas, Martin, Jan, Ogilvie, Lesley M, Scanlon, Ian J, Springer, Caroline J
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Biological and medical sciences; Breast Neoplasms; Cell Line, Tumor; Drug Screening Assays, Antitumor; Female; Fluorine; gamma-Glutamyl Hydrolase - genetics; gamma-Glutamyl Hydrolase - metabolism; General aspects; Humans; Medical sciences; Mice; Mice, Nude; Mustard Compounds - chemical synthesis; Mustard Compounds - chemistry; Mustard Compounds - metabolism; Mustard Compounds - pharmacology; Neoplasm Transplantation; Pharmacology. Drug treatments; Prodrugs - chemical synthesis; Prodrugs - chemistry; Prodrugs - metabolism; Prodrugs - pharmacology; Structure-Activity Relationship; Transplantation, Heterologous
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0502182

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.