New Mustard Prodrugs for Antibody-Directed Enzyme Prodrug Therapy:  Alternatives to the Amide Link

Antibody-directed enzyme prodrug therapy (ADEPT) is a two-step approach for the treatment of cancer which seeks to generate a potent cytotoxic agent selectively at a tumor site. In this work described the cytotoxic agent is generated by the action of an enzyme CPG2 on a relatively nontoxic prodrug....

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Bibliographic Details
Published in:Journal of medicinal chemistry 1996-03, Vol.39 (5), p.1100-1105
Main Authors: Dowell, Robert I, Springer, Caroline J, Davies, David H, Hadley, Elizabeth M, Burke, Philip J, Boyle, F. Thomas, Melton, Roger G, Connors, Thomas A, Blakey, David C, Mauger, Anthony B
Format: Article
Language:English
Subjects:
Aniline Mustard - analogs & derivatives
Aniline Mustard - chemical synthesis
Aniline Mustard - metabolism
Aniline Mustard - pharmacology
Antineoplastic agents
Antineoplastic Agents - chemical synthesis
Biological and medical sciences
Cell Death
Cell Division - drug effects
Chemotherapy
Colorectal Neoplasms - pathology
gamma-Glutamyl Hydrolase - metabolism
Humans
Immunotoxins
Medical sciences
Molecular Structure
Pharmacology. Drug treatments
Prodrugs - chemical synthesis
Tumor Cells, Cultured
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Summary:Antibody-directed enzyme prodrug therapy (ADEPT) is a two-step approach for the treatment of cancer which seeks to generate a potent cytotoxic agent selectively at a tumor site. In this work described the cytotoxic agent is generated by the action of an enzyme CPG2 on a relatively nontoxic prodrug. The prodrug 1 currently on clinical trial is a benzamide and is cleaved by CPG2 to a benzoic acid mustard drug 1a. We have synthesized a series of new prodrugs 3−8 where the benzamide link has been replaced by, for example, carbamate or ureido. Some of these alternative links have been shown to be good substrates for CPG2 and therefore new candidates for ADEPT. The active drugs 3a and 4a derived from the best of these prodrugs are potent cytotoxic agents (1−2 μM) some 100 times more than 1a. The prodrugs 3 and 4 are some 100−200-fold less cytotoxic, in a proliferating cell assay, than their corresponding active drugs 3a and 4a.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm950671l