RESUMO
N-sulfonated oversulfated chondroitin sulfate (NS-OSCS), recently reported as a potential threat to the heparin supply, was prepared along with its intermediate derivatives. All compounds were spiked into marketplace heparin and subjected to United States Pharmacopeia (USP) identification assays for heparin (proton nuclear magnetic resonance [(1)H NMR], chromatographic identity, % galactosamine [%GalN], anti-factor IIa potency, and anti-factor Xa/IIa ratio). The U.S. Food and Drug Administration (FDA) strong-anionic exchange high-performance liquid chromatography (SAX-HPLC) method resolved NS-OSCS from heparin and OSCS and had a limit of detection of 0.26% (w/w) NS-OSCS. The %GalN test was sensitive to the presence of NS-OSCS in heparin. Therefore, current USP heparin monograph tests (i.e., SAX-HPLC and %GalN) detect the presence of NS-OSCS in heparin.
Assuntos
Anticoagulantes/química , Sulfatos de Condroitina/análise , Contaminação de Medicamentos , Heparina/química , Indicadores e Reagentes/análise , Resinas de Troca Aniônica , Anticoagulantes/farmacologia , Sulfatos de Condroitina/química , Sulfatos de Condroitina/toxicidade , Cromatografia Líquida de Alta Pressão , Dimetilformamida/química , Contaminação de Medicamentos/prevenção & controle , Galactosamina/análise , Heparina/farmacologia , Hidrazinas/química , Indicadores e Reagentes/química , Indicadores e Reagentes/toxicidade , Limite de Detecção , Espectroscopia de Prótons por Ressonância Magnética , Controle de Qualidade , Estados Unidos , United States Food and Drug AdministrationRESUMO
An in silico screen of the NIH Molecular Library Small Molecule Repository (MLSMR) of â¼350000 compounds and confirmatory bioassays led to identification of chaetochromin A (1) as an inhibitor of botulinum neurotoxin serotype A (BoNT A). Subsequent acquisition and testing of analogues of 1 uncovered two compounds, talaroderxines A (2) and B (3), with improved activity. These are the first fungal metabolites reported to exhibit BoNT/A inhibitory activity.