Synthesis and biological evaluation of indenoisoquinolines that inhibit both tyrosyl-DNA phosphodiesterase I (Tdp1) and topoisomerase I (Top1).
J Med Chem
; 56(1): 182-200, 2013 Jan 10.
Article
em En
| MEDLINE
| ID: mdl-23259865
ABSTRACT
Tyrosyl-DNA phosphodiesterase I (Tdp1) plays a key role in the repair of damaged DNA resulting from the topoisomerase I (Top1) inhibitor camptothecin and a variety of other DNA-damaging anticancer agents. This report documents the design, synthesis, and evaluation of new indenoisoquinolines that are dual inhibitors of both Tdp1 and Top1. Enzyme inhibitory data and cytotoxicity data from human cancer cell cultures were used to establish structure-activity relationships. The potencies of the indenoisoquinolines against Tdp1 ranged from 5 µM to 111 µM, which places the more active compounds among the most potent known inhibitors of this target. The cytotoxicity mean graph midpoints ranged from 0.02 to 2.34 µM. Dual Tdp1-Top1 inhibitors are of interest because the Top1 and Tdp1 inhibitory activities could theoretically work synergistically to create more effective anticancer agents.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Inibidores de Fosfodiesterase
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DNA Topoisomerases Tipo I
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Diester Fosfórico Hidrolases
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Inibidores da Topoisomerase I
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Indenos
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Isoquinolinas
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Antineoplásicos
Limite:
Humans
Idioma:
En
Revista:
J Med Chem
Ano de publicação:
2013
Tipo de documento:
Article