RESUMO
Since the 1950's, AMP-kinase (AMPK) has been used as a promising target for the development of antidiabetic drugs against Type 2 diabetes mellitus (T2D). Indeed, the canonical antidiabetic drug metformin recruits, at least partially, AMPK activation for its therapeutic effect. Herein we present design and synthesis of 20 novel relatively polar cyclic and acyclic dithioacetals of 2-(Het)arylchroman-6-carbaldehydes, 2-phenyl-1,4-benzodioxane-6-carbaldehyde, and 2-phenylbenzofuran-5-carbaldehyde, which were developed as potential AMPK activators. Three of the synthesized dithioacetals demonstrated significant enhancement (≥70%) of glucose uptake in rat L6 myotubes. Noteworthy, one of the dithioacetals, namely 4-(6-(1,3-dithian-2-yl)chroman-2-yl)pyridine, exhibited high potency comparing to other molecules. It increased the rate of glucose uptake in rat L6 myotubes and augmented insulin secretion from rat INS-1E cells in pharmacological relevant concentrations (up to 2 µM). Both effects were mediated by activation of AMPK. In addition, the compound showed excellent pharmacokinetic profile in healthy mice, including maximal oral bioavailability. Such bifunctionality (increased glucose uptake and insulin secretion) can be used as a starting point for the development of a novel class of antidiabetic drugs with dual activity that is relevant for T2D treatment.
Assuntos
Diabetes Mellitus Tipo 2 , Hipoglicemiantes , Ratos , Camundongos , Animais , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Proteínas Quinases Ativadas por AMP , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucose/farmacologia , Linhagem Celular , Fibras Musculares Esqueléticas , Insulina/farmacologiaRESUMO
The C2-WW-HECT-domain E3 ubiquitin ligase SMURF2 emerges as an important regulator of diverse cellular processes. To date, SMURF2-specific modulators were not developed. Here, we generated and investigated a set of SMURF2-targeting synthetic peptides and peptidomimetics designed to stimulate SMURF2's autoubiquitination and turnover via a disruption of the inhibitory intramolecular interaction between its C2 and HECT domains. The results revealed the effects of these molecules both in vitro and in cellulo at the nanomolar concentration range. Moreover, the data showed that targeting of SMURF2 with either these modifiers or SMURF2-specific shRNAs could accelerate cell growth in a cell-context-dependent manner. Intriguingly, a concomitant cell treatment with a selected SMURF2-targeting compound and the DNA-damaging drug etoposide markedly increased the cytotoxicity produced by this drug in growing cells. Altogether, these findings demonstrate that SMURF2 can be druggable through its self-destructive autoubiquitination, and inactivation of SMURF2 might be used to affect cell sensitivity to certain anticancer drugs.
Assuntos
Antineoplásicos/farmacologia , Desenvolvimento de Medicamentos , Inibidores Enzimáticos/farmacologia , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Five out of six people receive at least one antibiotic prescription per year. However, the ever-expanding use of antibiotics in medicine, agriculture, and food production has accelerated the evolution of antibiotic-resistant bacteria, which, in turn, made the development of novel antibiotics based on new molecular targets a priority in medicinal chemistry. One way of possibly combatting resistant bacterial infections is by inhibiting the copper transporters in prokaryotic cells. Copper is a key element within all living cells, but it can be toxic in excess. Both eukaryotic and prokaryotic cells have developed distinct copper regulation systems to prevent its toxicity. Therefore, selectively targeting the prokaryotic copper regulation system might be an initial step in developing next-generation antibiotics. One such system is the Gram-negative bacterial CusCFBA efflux system. CusB is a key protein in this system and was previously reported to play an important role in opening the channel for efflux via significant structural changes upon copper binding while also controlling the assembly and disassembly process of the entire channel. In this study, we aimed to develop novel peptide copper channel blockers, designed by in silico calculations based on the structure of CusB. Using a combination of magnetic resonance spectroscopy and various biochemical methods, we found a lead peptide that promotes copper-induced cell toxicity. Targeting copper transport in bacteria has not yet been pursued as an antibiotic mechanism of action. Thus, our study lays the foundation for discovering novel antibiotics.