Abstract
The design and synthesis of potent thiocarbamate inhibitors for carboxypeptidase G2 are described. The best thiocarbamate inhibitor N-(p-methoxybenzenethiocarbonyl)amino-L-glutamic acid 6d, chosen for preliminary investigations of in vitro antibody-directed enzyme prodrug therapy (ADEPT), abrogated the cytotoxicity of a combination of A5B7-carboxypeptidase G2 conjugate and prodrug PGP (N-p-{N,N-bis (2-chloroethyl)amino}phenoxycarbonyl-L-glutamate) toward LS174T cells. This is the first report of a small-molecule enzyme inhibitor proposed for use in conjunction with the ADEPT approach.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aniline Mustard / analogs & derivatives
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Aniline Mustard / pharmacology
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Antibodies / pharmacology*
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Antineoplastic Agents / pharmacology*
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Chromatography, Thin Layer
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Inhibitory Concentration 50
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Magnetic Resonance Spectroscopy
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Prodrugs / pharmacology*
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Structure-Activity Relationship
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Tumor Cells, Cultured
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gamma-Glutamyl Hydrolase / antagonists & inhibitors*
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gamma-Glutamyl Hydrolase / pharmacology
Substances
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(4-(N,N-bis(2-chloroethyl)amino)phenoxycarbonyl)glutamic acid
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Antibodies
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Antineoplastic Agents
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Enzyme Inhibitors
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Prodrugs
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Aniline Mustard
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gamma-Glutamyl Hydrolase