Acidotropic properties of synthetic hexahydropyridoindole antioxidants
Abstract:
In acidic intracellular organelles, sequestration via a proton-trapping mechanism is observed for many amine-containing drugs. It may be related to several adverse effects of a drug, yet accumulation of amines bearing antioxidant functionality may provide efficient protection of these compartments. In the present study, a possible proton-trapping mechanism of the novel antioxidant reference stobadine (STO) and its selected derivatives was investigated also with regard to their antioxidant properties, using BV-2 microglia. Unlike its 2-ethoxycarbonyl-8-methoxy derivative EC-STO (pKa1 4.95, pKa2 -3.58), STO, bearing weakly basic piperidine moiety (pKa2 9.03), induced vacuolar response in the cells. EC-STO, compared to STO, failed to provide better protection against oxidative damage induced by tert-butyl hydroperoxide (BHP), and that in spite of its predicted improved bioavailability and antioxidant properties. However, disruption of the lysosomal proton gradient abolished the efficacy of STO in suppressing oxidants generation and injury of the cells. NT-STO, the 6-nitro derivative of stobadine, lacking antiradical efficacy, showed a lower effect in protecting the cells against BHP. In conclusion, our study suggests that weakly basic hexahydropyridoindoles may act as lysosomotropic compounds. Furthermore, their weakly basic characteristics may contribute to their improved efficacy in suppressing peroxidative processes within lysosomes, and thus possibly combating ageing-related pathologies.
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