Hypoxia-activated prodrugs: substituent effects on the properties of nitro seco-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (nitroCBI) prodrugs of DNA minor groove alkylating agents.
J Med Chem
; 52(22): 7258-72, 2009 Nov 26.
Article
em En
| MEDLINE
| ID: mdl-19877646
ABSTRACT
Nitrochloromethylbenzindolines (nitroCBIs) are a new class of hypoxia-activated prodrugs for antitumor therapy. The recently reported prototypes undergo hypoxia-selective metabolism to form potent DNA minor groove alkylating agents and are selectively toxic to some but not all hypoxic tumor cell lines. Here we report a series of 31 analogues that bear an extra electron-withdrawing substituent that serves to raise the one-electron reduction potential of the nitroCBI. We identify a subset of compounds, those with a basic side chain and sulfonamide or carboxamide substituent, that have consistently high hypoxic selectivity. The best of these, with a 7-sulfonamide substituent, displays hypoxic cytotoxicity ratios of 275 and 330 in Skov3 and HT29 human tumor cell lines, respectively. This compound (28) is efficiently and selectively metabolized to the corresponding aminoCBI, is selectively cytotoxic under hypoxia in all 11 cell lines examined, and demonstrates activity against hypoxic tumor cells in a human tumor xenograft in vivo.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
DNA
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Pró-Fármacos
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Antineoplásicos Alquilantes
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Indóis
Limite:
Animals
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Female
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Humans
Idioma:
En
Ano de publicação:
2009
Tipo de documento:
Article