Exploration of 2-((Pyridin-4-ylmethyl)amino)nicotinamide Derivatives as Potent Reversal Agents against P-Glycoprotein-Mediated Multidrug Resistance.
J Med Chem
; 60(7): 2930-2943, 2017 04 13.
Article
em En
| MEDLINE
| ID: mdl-28301155
ABSTRACT
Overexpression of the ATP-binding cassette (ABC) transport proteins, like ABCB1, commonly referred to as P-glycoprotein (P-gp), initiates active efflux of a broad spectrum of unrelated chemotherapeutic drugs in structure and function, leading to chemotherapy failure. A series of 2-((pyridin-4-ylmethyl)amino)nicotinamide derivatives as potent reversal agents against P-glycoprotein-mediated multidrug resistance (MDR) were designed and synthesized. The majority of target compounds displayed great reversal potency, especially 9n. In-depth studies demonstrated 9n has high potency (EC50 = 119.6 ± 6.9 nM), low cytotoxicity, and long duration (>24 h) in reversing adriamycin (ADM) resistance in K562/A02 cells. 9n also improved the effects of other cytotoxic agents related to MDR, increased accumulation of ADM, interrupted P-gp-mediated Rh123 efflux function, and suppressed P-gp ATPase activity in K562/A02 MDR cells. The Western blot analysis indicated that the MDR reversal by 9n was not due to a decrease in protein expression. Besides, the effect of CYP3A4 was not influenced by 9n, avoiding the toxicity caused by drug interactions. The study yielded 9n with superior properties compared to the classical inhibitor verapamil (VRP) and leading compound apatinib.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Doxorrubicina
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Niacinamida
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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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Antibióticos Antineoplásicos
Limite:
Humans
Idioma:
En
Revista:
J Med Chem
Ano de publicação:
2017
Tipo de documento:
Article