A Novel Approach Toward Microfluidic Drug Metabolite Synthesis – Electrosynthetic Methodology Simulating Cytochrome (CYP450) Oxidation
Poster Aug 05, 2014
Romain Stalder, Gregory P. Roth and Philip Podmore
It has been found that the electrochemical cell allows for clean oxidation and subsequent trapping of reactive intermediates with glutathione, thus mimicking mammalian hepatic transformation. In this particular study, the electrochemical cell enables four different types of reactions determined by the chemical structure of each drug: (1) aromatic hydroxylation, (2) aliphatic hydroxylation, (3) sulfoxidation and (4) glutathione conjugation. The metabolites are synthesized on the scale of 10 mg to 100 mg per hour of continuous flow, allowing for purification and full structural elucidation. This is particularly important because regioisomeric structural species are directly observed by NMR. This aspect is difficult to assess using typical in vitro microsomal or in vivo plasma bioassay with LC/MS analysis or emerging microscale EC/MS techniques. Therefore, the preparative nature of this new electrosynthesis module constitutes one of it great advantages, alongside its ease of use and versatility.
Plasmodium falciparum is evolving resistance to Artemisinin Combination Therapy. The gene with the strongest association with resistance is K13. K13 is an ortholog of the well characterized transcriptional regulator Keap1. In this work we transcriptionally characterized a mutant with a transposon inserted in the K13 promoter region which results in dysregulation of K13 at 2 points of the intraerythrocytic cycle of the life-cycle to identify the processes regulated by K13.READ MORE