RESUMO
Considering the frequent use of netupitant in polytherapy, the elucidation of its oxidative metabolization pattern is of major importance. However, there is a lack of published research on the redox behavior of this novel neurokinin-1 receptor antagonist. Therefore, this study was performed to simulate the intensive hepatic biotransformation of netupitant using an electrochemically driven method. Most of the known enzyme-mediated reactions occurring in the liver (i.e., N-dealkylation, hydroxylation, and N-oxidation) were successfully mimicked by the electrolytic cell using a boron-doped diamond working electrode. The products were separated by reversed-phase high-performance liquid chromatography and identified by high-resolution mass spectrometry. Aside from its ability to pinpoint formerly unknown metabolites that could be responsible for the known side effects of netupitant or connected with any new perspective concerning future therapeutic indications, this electrochemical process also represents a facile alternative for the synthesis of oxidation products for further in vitro and in vivo studies.
RESUMO
Unfortunately the name of Jean Jacques Vanden Eynde was missing as co-author of this contribution. The correct list of authors is: Ioan O. Neaga, Stephanie Hambye, Ede Bodoki, Claudio Palmieri, Jean Jacques Vanden Eynde, Eugénie Ansseau, Alexandra Belayew, Radu Oprean, Bertrand Blankert.
RESUMO
Myotonic dystrophy type 1 (DM1) is an autosomal dominantly inherited degenerative disease with a slow progression. At the present, there is no commercially available treatment, but sustained effort is currently undertaken for the development of a promising lead compound. In the present paper we report the development of a fast, versatile, and cost-effective affinity capillary electrophoresis (ACE) method for the screening and identification of potential drug candidates targeting pathological ARN probes relevant for DM1. The affinity studies were conducted in physiologically relevant conditions using 50 mM HEPES buffer (pH 7.4) in a fused silica capillary dynamically coated with poly(ethylene oxide), by testing a library of potential ligands against (CUG)50 RNA as target probe with a total run time of 4-5 h/ligand. For the most promising ligands, their affinity parameters were assessed and some results formerly reported on the affinity of pentamidine (PTMD) and neomycin against CUG repeats were confirmed. To the best of the authors' knowledge, the estimated binding stoichiometry for some of the tested compounds (i.e., ~ 121:1 for PTMD against the tested RNA probe) is reported for the first time. Additionally, the potential of a novel pentamidine like compound, namely 1,2-ethane bis-1-amino-4-benzamidine (EBAB) with much lower in vivo toxicity than its parent compound has also been confirmed studying its effect on a live cell model by fluorescence microscopy. Further tests, such as the evaluation of the rescue in the mis-splicing of the involved genes, can be performed to corroborate the potential therapeutic value of EBAB in DM1 treatment. Graphical abstract á .