Abstract
Cyclic and acyclic nitroaryl phosphoramide mustard analogues were activated by E. coli nitroreductase, an enzyme explored in GDEPT. The more active acyclic 4-nitrobenzyl phosphoramide mustard (7) showed 167 500x selective cytotoxicity toward nitroreductase-expressing V79 cells with an IC(50) as low as 0.4 nM. This is about 100x more active and 27x more selective than CB1954 (1). The superior activity was attributed to its better substrate activity (k(cat)/K(m) 19x better than 1) and/or excellent cytotoxicity of phosphoramide mustard released.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents, Alkylating / chemical synthesis*
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Antineoplastic Agents, Alkylating / pharmacology
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Cell Line
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Cell Line, Tumor
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Cricetinae
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Cricetulus
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Cyclophosphamide / analogs & derivatives
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Cyclophosphamide / chemical synthesis
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Cyclophosphamide / pharmacology
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Enzyme Activators / chemical synthesis*
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Enzyme Activators / pharmacology
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Escherichia coli / enzymology*
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Fibroblasts / cytology
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Fibroblasts / drug effects
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Fibroblasts / metabolism
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Humans
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Nitro Compounds / chemical synthesis*
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Nitro Compounds / pharmacology
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Nitroreductases / metabolism*
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Oxidation-Reduction
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Phosphoramide Mustards / chemical synthesis*
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Phosphoramide Mustards / pharmacology
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Prodrugs / chemical synthesis*
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Prodrugs / pharmacology
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Structure-Activity Relationship
Substances
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Antineoplastic Agents, Alkylating
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Enzyme Activators
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Nitro Compounds
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Phosphoramide Mustards
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Prodrugs
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Cyclophosphamide
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Nitroreductases