Design, synthesis, and biological evaluation of pyrrolobenzodiazepine-containing hypoxia-activated prodrugs.
Bioorg Med Chem Lett
; 27(23): 5300-5304, 2017 12 01.
Article
em En
| MEDLINE
| ID: mdl-29079474
ABSTRACT
The ability of various pyrrolobenzodiazepine(PBD)-containing cytotoxic compounds to function as hypoxia-activated prodrugs was assessed. These molecules incorporated a 1-methyl-2-nitro-1H-imidazole hypoxia-activated trigger (present in the clinically evaluated compound TH-302) in a manner that masked a reactive imine moiety required for cytotoxic activity. Incubation of the prodrugs with cytochrome P450-reductase under normoxic and hypoxic conditions revealed that some, but not all, were efficient substrates for the enzyme. In these experiments, prodrugs derived from PBD-monomers underwent rapid conversion to the parent cytotoxic compounds under low-oxygen conditions while related PBD-dimers did not. The ability of a given prodrug to function as an efficient cytochrome P450-reductase substrate correlated with the ratio of cytotoxic potencies measured for the compound against NCI460 cells under normoxic and hypoxic conditions.
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MEDLINE
Assunto principal:
Pirróis
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Benzodiazepinas
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Pró-Fármacos
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Desenho de Fármacos
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Hipóxia
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article