RESUMO
Three new compounds named leporizines A-C have been isolated from an Aspergillus sp. strain. Their structures were elucidated by analysis of 1D and 2D NMR spectra. Leporizines A and B were isolated during dereplication of hits from a high-throughput screening campaign for correctors of the cystic fibrosis transmembrane conductance regulator (CFTR), and leporizine C was isolated while preparing additional material for characterization of leporizines A and B. CFTR activity observed for leporizines A and B was highly correlated with cell toxicity and was determined to be a nonspecific effect. Leporizine C was not cytotoxic to cells and did not elicit a response in the CFTR assays. To the best of our knowledge, leporizines A-C represent the first examples of this unusual epithiodiketopiperazine skeleton.
Assuntos
Antineoplásicos/isolamento & purificação , Aspergillus/química , Dicetopiperazinas/isolamento & purificação , Antineoplásicos/química , Antineoplásicos/farmacologia , Regulador de Condutância Transmembrana em Fibrose Cística/efeitos dos fármacos , Dicetopiperazinas/química , Dicetopiperazinas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Estrutura Molecular , Montana , Mutação , Ressonância Magnética Nuclear Biomolecular , Mucosa RespiratóriaAssuntos
Actinomycetales/metabolismo , Antraquinonas/farmacologia , Anti-Infecciosos/farmacologia , Antraquinonas/isolamento & purificação , Anti-Infecciosos/isolamento & purificação , Linhagem Celular , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Células Hep G2 , Humanos , Testes de Sensibilidade MicrobianaRESUMO
A new series of 5-(pyridinon-1-yl)indazoles with MCH-1 antagonist activity were synthesized. Potential cardiovascular risk for these compounds was assessed based upon their interaction with the hERG potassium channel in a mini-patch clamp assay. Selected compounds were studied in a 5-day diet-induced obese mouse model to evaluate their potential use as weight loss agents. Structural modification of the 5-(pyridinon-1-yl)indazoles to give 5-(furopyridinon-5-yl)indazoles provided compounds with enhanced pharmacokinetic properties and improved efficacy.
Assuntos
Indazóis/farmacologia , Obesidade/tratamento farmacológico , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Animais , Fármacos Antiobesidade/química , Fármacos Antiobesidade/farmacologia , Doenças Cardiovasculares/induzido quimicamente , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Humanos , Indazóis/farmacocinética , Indazóis/uso terapêutico , Camundongos , Relação Estrutura-AtividadeRESUMO
Three new antibiotics, neopyrrolomycins B (1), C (2), and D (3), with potent activity against Gram-positive pathogens were discovered. They exhibited MIC values < 1 microg/mL versus a number of resistant strains. The compounds were obtained from the ethyl acetate extracts of a Streptomyces sp. after purification by column chromatography and RP-HPLC. Their structures were elucidated using X-ray crystallography (1) and NMR spectroscopy (2 and 3).
Assuntos
Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Streptomyces/química , Antibacterianos/química , Cristalografia por Raios X , Farmacorresistência Bacteriana/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Enterococcus faecium/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Humanos , Klebsiella pneumoniae/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Conformação Molecular , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Pseudomonas aeruginosa/efeitos dos fármacos , Pirróis/química , Pirróis/isolamento & purificação , Pirróis/farmacologia , Streptococcus pneumoniae/efeitos dos fármacos , Vancomicina/farmacologiaRESUMO
Resistance to currently available antibiotics has become a widely recognized crisis in the medical community. To address this, many companies and researchers are refocusing their attention towards natural products, which have an excellent track record of producing effective antibacterial drugs. The AMRI natural product library was screened for activity against multi-drug resistant Staphylococcus aureus (MDRSA). The active samples were counter screened for cytotoxicity against the human hepatocellular carcinoma HepG2 cell line to determine an in vitro therapeutic index (in vitro TI). Those samples with a high in vitro TI were selected for fractionation and dereplication. This led to the discovery of a new anthracycline structure. This metabolite, named mutactimycin E (1), exhibited moderate activity against several gram positive organisms. Here we report the isolation, structure elucidation and biological activities of this new compound.