Discovery and synthesis of 3- and 21-substituted fusidic acid derivatives as reversal agents of P-glycoprotein-mediated multidrug resistance.
Eur J Med Chem
; 182: 111668, 2019 Nov 15.
Article
em En
| MEDLINE
| ID: mdl-31505451
ABSTRACT
In this study, we synthesized 23 fusidic acid (FA) derivatives and screened them for tumor drug resistance reversal activity and cytotoxicity toward the KBV (multidrug-resistant oral epidermoid carcinoma) cell line based on MTT assay. Tumor resistance reversal activity of fusidic acid (FA) derivatives was discovered for the first time. Our results showed that compound 1 enhanced the cytotoxicity of paclitaxel toward the drug-resistant KBV cells at a concentration of 5⯵M. And compound 1 sensitized KBV cells toward paclitaxel in arresting cells in the G2/M phase and inducing cell apoptosis. Further researches showed that compound 1 inhibited the drug efflux activity of P-glycoprotein (P-gp) by increasing the ATPase activity of P-gp without affecting its expression. The structure-activity relationships (SARs) of the FA derivatives were also preliminarily investigated. Our findings indicate that compound 1 is a promising lead compound for designing FA derivatives with improved tumor drug resistance reversal activity in the future.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Membro 1 da Subfamília B de Cassetes de Ligação de ATP
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Resistência a Múltiplos Medicamentos
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Resistencia a Medicamentos Antineoplásicos
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Descoberta de Drogas
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Ácido Fusídico
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Antineoplásicos
Limite:
Humans
Idioma:
En
Revista:
Eur J Med Chem
Ano de publicação:
2019
Tipo de documento:
Article