RESUMO
Halogenated diarylacetylenes that possess fluorine or chlorine substituents in one aryl ring and N-methylamino or N,N-dimethylamino in the other aryl ring inhibit the proliferation of LS174T colon cancer cells through the repression of c-myc expression and induction of the cyclin-dependent kinase inhibitor-1 (i.e., p21(Wif1/Cip1)) and represent potentially useful antineoplastic agents.
Assuntos
Alcinos/química , Antineoplásicos/farmacologia , Hidrocarbonetos Clorados/farmacologia , Hidrocarbonetos Fluorados/farmacologia , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Halogenação , Humanos , Hidrocarbonetos Clorados/síntese química , Hidrocarbonetos Clorados/química , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/química , Modelos Moleculares , Estrutura Molecular , Proteínas Proto-Oncogênicas c-myc/biossíntese , Relação Estrutura-AtividadeRESUMO
Adenosine monophosphate-activated kinase (AMPK) plays a central role in regulating energy homeostasis in eukaryotic cells. AMPK also regulates lipid synthesis by inhibiting acetyl-CoA carboxylase (ACC) and regulates mTOR signaling by activating TSC2. Due to its important roles in cell metabolism, AMPK is an attractive target for metabolic diseases, such as type II diabetes and obesity. AMPK activators, such as metformin, that are used for diabetes treatment are also effective anticancer agents. However, the efficacies of many known AMPK activators are relatively low. For example, metformin activates AMPK at millimolar levels. In this study, we identified a novel family of AMPK activators, namely fluorinated N,N'-diarylureas, that activate AMPK at 1-3µM concentrations. These novel agents strongly inhibit the proliferation of colon cancer cells. We studied the potential mechanisms of these agents, performed a structure-activity relationship (SAR) study and identified several fluorinated N,N'-diarylureas as potent AMPK activators.
