RESUMO
Metformin is a treatment of choice for patients with type 2 diabetes. Its action involves the phosphorylation of 5'-adenosine monophosphate activated protein kinase (AMPK), leading to inhibition of liver gluconeogenesis. The effects of a novel chemical compound derived from metformin, HL271, on molecular and physiological actions involving AMPK and rhythmically-expressed circadian clock genes were investigated. HL271 potently activated AMPK in a dose-dependent manner, and produced shortening of the circadian period and enhanced degradation of the clock genes PER2 and CRY1. Although the molecular effects of HL271 resembled those of metformin, it produced different physiological effects in mice with diet-induced obesity. HL271 did not elicit glucose-lowering or insulin-sensitizing effects, possibly because of altered regulation of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase 1. This indicated that, although HL271 acted on circadian clock machinery through a similar molecular mechanism to metformin, it differed in its systemic effect on glucose and lipid metabolite regulations.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Proteínas de Ciclo Celular/metabolismo , Relógios Circadianos/efeitos dos fármacos , Metformina/análogos & derivados , Metformina/farmacologia , Obesidade/metabolismo , Animais , Linhagem Celular , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/fisiologia , Células Hep G2 , Humanos , Hipoglicemiantes , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Células NIH 3T3 , Relação Estrutura-Atividade , Resultado do TratamentoRESUMO
The post-polyketide synthase modification of geldanamycin (1) biosynthesis is of interest as a means of introducing structural diversity into the compound. From the inactivation of a gene encoding carbamoyltransferase, we demonstrated that the C-17 hydroxylation and the C-21 oxidation precede O-carbamoylation and that the hypothetical progeldanamycin does not possess a double bond at C-4 and C-5. More importantly, our result revealed new intermediates 4,5-dihydro-7-O-descarbamoyl-7-hydroxygeldanamycin (3) and 4,5-dihydrogeldanamycin (5), indicating that O-carbamoylation occurs prior to the C-4,5 cis double bond formation in geldanamycin biosynthesis.