Nitro seco analogues of the duocarmycins containing sulfonate leaving groups as hypoxia-activated prodrugs for cancer therapy.
J Med Chem
; 55(6): 2780-802, 2012 Mar 22.
Article
em En
| MEDLINE
| ID: mdl-22339090
ABSTRACT
The synthesis of 19 (5-nitro-2,3-dihydro-1H-benzo[e]indol-1-yl)methyl sulfonate prodrugs containing sulfonate leaving groups and 7-substituted electron-withdrawing groups is reported. These were designed to undergo hypoxia-selective metabolism to form potent DNA minor groove-alkylating agents. Analogues 17 and 24, containing the benzyl sulfonate leaving group and a neutral DNA minor groove-binding side chain, displayed hypoxic cytotoxicity ratios (HCRs) of >1000 in HT29 human cancer cells in vitro in an antiproliferative assay. Four analogues maintained large HCRs across a panel of eight human cancer cell lines. In a clonogenic assay, 19 showed an HCR of 4090 in HT29 cells. Ten soluble phosphate preprodrugs were also prepared and evaluated in vivo, alone and in combination with radiation in SiHa human tumor xenografts at a nontoxic dose. Compounds 34 and 39 displayed hypoxic log(10) cell kills (LCKs) of 1.78 and 2.71, respectively, equivalent or superior activity to previously reported chloride or bromide analogues, thus showing outstanding promise as hypoxia-activated prodrugs.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Ácidos Sulfônicos
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Pró-Fármacos
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Antineoplásicos Alquilantes
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Indóis
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Neoplasias
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Nitrocompostos
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article