Anti-Leukemic
Activity of Ubiquinone-Based Compounds
Targeting Trans-plasma Membrane Electron Transport
- Publication date
- Publisher
Abstract
Trans-plasma
membrane electron transport (tPMET) is a ubiquinone-dependent
cell survival pathway for maintaining intracellular redox homeostasis
in rapidly dividing cells. To target this pathway, fifteen ubiquinone-based
compounds were designed and synthesized to position at the plasma
membrane and disrupt tPMET. We established that quaternary ammonium
salt moieties carrying highly hindered, positive electronic charges
located to the plasma membrane. A ten-carbon chain linked to these moieties was effective at positioning the redox-active ubiquinone-like function
within the lipid bilayer to disrupt tPMET in human leukemic cells
(IC<sub>50</sub> 9 ± 1 μM). TPMET inhibition alone was
not sufficient to induce significant cell death, but positively charged
compounds could also enter the cell and disrupt intracellular redox
balance, distinct from their effects on mitochondrial electron transport.
The synergistic effect of tPMET inhibition plus intracellular redox
disruption gave strong antiproliferative activity (IC<sub>50</sub> 2 ± 0.2 μM). Positively charged ubiquinone-based compounds
inhibit human leukemic cell growth