3-Aminomethyl derivatives of 4,11-dihydroxynaphtho[2,3-f]indole-5,10-dione for circumvention of anticancer drug resistance.
Bioorg Med Chem
; 13(6): 2285-91, 2005 Mar 15.
Article
em En
| MEDLINE
| ID: mdl-15727877
ABSTRACT
A series of 3-aminomethyl derivatives of 4,11-dihydroxynaphtho[2,3-f]indole-5,10-dione was synthesized by Mannich reaction or by the transamination of 3-dimethylaminomethyl 4,11-dihydroxy- or 4,11-dimethoxynaphtho[2,3-f]indole-5,10-dione. The potency of novel derivatives was tested on a National Cancer Institute panel of 60 human tumor cell lines as well as in cells with genetically defined determinants of cytotoxic drug resistance, P-glycoprotein (Pgp) expression, and p53 inactivation. Mannich derivatives of 4,11-dihydroxynaphtho[2,3-f]indole-5,10-dione with an additional amino function in their side chain, demonstrated equal cytotoxicity against the parental K562 leukemia cells and their Pgp-positive subline, whereas the latter showed approximately 7-fold resistance to adriamycin, a Pgp transported drug. 3-(1-Piperazinyl)methyl and 3-(quinuclidin-3-yl)aminomethyl derivatives of 4,11-dihydroxynaphtho[2,3-f]indole-5,10-dione killed HCT116 colon carcinoma cells (carrying wild type p53) and their p53-null variant within the similar range of concentrations. We conclude that Mannich modification of 4,11-dihydroxynaphtho[2,3-f]indole-5,10-dione, especially when cyclic diamine (e.g., piperazine, quinuclidine) is used, confers an important feature to the resulting compounds, namely, the potency for tumor cells otherwise resistant to a variety of anticancer drugs.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Resistencia a Medicamentos Antineoplásicos
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Indóis
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Naftalenos
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Antineoplásicos
Limite:
Humans
Idioma:
En
Ano de publicação:
2005
Tipo de documento:
Article