Potent and highly selective hypoxia-activated achiral phosphoramidate mustards as anticancer drugs.
J Med Chem
; 51(8): 2412-20, 2008 Apr 24.
Article
em En
| MEDLINE
| ID: mdl-18257544
ABSTRACT
A series of achiral hypoxia-activated prodrugs were synthesized on the basis of the DNA cross-linking toxin of the prodrug, ifosfamide. The hypoxia-selective cytotoxicity of several of the compounds was improved over previously reported racemic mixtures of chiral bioreductive phosphoramidate prodrugs. Prodrugs activated by 2-nitroimidazole reduction demonstrated up to 400-fold enhanced cytotoxicity toward H460 cells in culture under hypoxia versus their potency under aerobic conditions. Compounds were further assessed for their stability to cytochrome P450 metabolism using a liver microsome assay. The 2-nitroimidazole containing lead compound 3b (TH-302) was selectively potent under hypoxia and stable to liver microsomes. It was active in an in vivo MIA PaCa-2 pancreatic cancer orthotopic xenograft model as a monotherapy and demonstrated dramatic efficacy when used in combination with gemcitabine, extending survival with one of eight animals tumor free at day-44. Compound 3b has emerged as a promising antitumor agent that shows excellent in vivo efficacy and is currently being evaluated in the clinic.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Ácidos Fosfóricos
/
Hipóxia Celular
/
Amidas
/
Antineoplásicos
Idioma:
En
Ano de publicação:
2008
Tipo de documento:
Article