RESUMO
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.
Assuntos
Amidas/química , Fosfofrutoquinase-2/antagonistas & inibidores , Quinoxalinas/química , Quinoxalinas/farmacologia , Sulfonamidas/química , Células HCT116 , Humanos , Cinética , SolubilidadeRESUMO
Energy and biomass production in cancer cells are largely supported by aerobic glycolysis in what is called the Warburg effect. The process is regulated by key enzymes, among which phosphofructokinase PFK-2 plays a significant role by producing fructose-2,6-biphosphate; the most potent activator of the glycolysis rate-limiting step performed by phosphofructokinase PFK-1. Herein, the synthesis, biological evaluation and structure-activity relationship of novel inhibitors of 6-phosphofructo-2-kinase/fructose-2,6-biphosphataseâ 3 (PFKFB3), which is the ubiquitous and hypoxia-induced isoform of PFK-2, are reported. X-ray crystallography and docking were instrumental in the design and optimisation of a series of N-aryl 6-aminoquinoxalines. The most potent representative, N-(4-methanesulfonylpyridin-3-yl)-8-(3-methyl-1-benzothiophen-5-yl)quinoxalin-6-amine, displayed an IC50 of 14â nm for the target and an IC50 of 0.49â µm for fructose-2,6-biphosphate production in human colon carcinoma HCT116 cells. This work provides a new entry in the field of PFKFB3 inhibitors with potential for development in oncology.
Assuntos
Descoberta de Drogas , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Fosfofrutoquinase-2/antagonistas & inibidores , Quinoxalinas/química , Quinoxalinas/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Células HCT116 , Humanos , Ácido Láctico/antagonistas & inibidores , Ácido Láctico/biossíntese , Modelos Moleculares , Estrutura Molecular , Fosfofrutoquinase-2/metabolismo , Quinoxalinas/síntese química , Relação Estrutura-AtividadeRESUMO
A series of novel 2'-C-methylribonucleosides, involving 5-iodo and 5-alkynyl uridine analogues as well as related bicyclic furano- and pyrrolo[2,3-d]pyrimidinone compounds, has been synthesized and evaluated for their inhibitory effect on replication of the hepatitis C virus (HCV). The new nucleoside analogues did not show meaningful anti-HCV activity.
Assuntos
Antivirais/química , Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Pirimidinas/química , Pirimidinas/farmacologia , Ribonucleosídeos/química , Ribonucleosídeos/farmacologia , Antivirais/síntese química , Linhagem Celular , Hepatite C/tratamento farmacológico , Humanos , Pirimidinas/síntese química , Pirróis/síntese química , Pirróis/química , Pirróis/farmacologia , Ribonucleosídeos/síntese químicaRESUMO
A series of novel derivatives of 2'-C-beta-methylcytidine, involving nucleosides modified in the "upper part" of the pyrimidine base (N(4)- and/or 5-position), has been synthesized and evaluated for their inhibitory effect on in vitro replication of the hepatitis C virus and the yellow fever virus (both Flaviviridae).