Synthesis of amide and sulfonamide substituted N-aryl 6-aminoquinoxalines as PFKFB3 inhibitors with improved physicochemical properties.
Bioorg Med Chem Lett
; 29(4): 646-653, 2019 02 15.
Article
em En
| MEDLINE
| ID: mdl-30626557
ABSTRACT
In oncology, the "Warburg effect" describes the elevated production of energy by glycolysis in cancer cells. The ubiquitous and hypoxia-induced 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) plays a noteworthy role in the regulation of glycolysis by producing fructose-2,6-biphosphate (F-2,6-BP), a potent activator of the glycolysis rate-limiting phosphofructokinase PFK-1. Series of amides and sulfonamides derivatives based on a N-aryl 6-aminoquinoxaline scaffold were synthesized and tested for their inhibition of PFKFB3 in vitro in a biochemical assay as well as in HCT116 cells. The carboxamide series displayed satisfactory kinetic solubility and metabolic stability, and within this class, potent lead compounds with low nanomolar activity have been identified with a suitable profile for further in vivo evaluation.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Quinoxalinas
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Sulfonamidas
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Fosfofrutoquinase-2
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Amidas
Limite:
Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article