Anti-Leukemic Activity of Ubiquinone-Based Compounds Targeting Trans-plasma Membrane Electron Transport

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 (IC₅₀ 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 (IC₅₀ 2 ± 0.2 μM). Positively charged ubiquinone-based compounds inhibit human leukemic cell growth

Anti-Leukemic Activity of Ubiquinone-Based Compounds Targeting Trans-plasma Membrane Electron Transport

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 (IC₅₀ 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 (IC₅₀ 2 ± 0.2 μM). Positively charged ubiquinone-based compounds inhibit human leukemic cell growth

Nortriketones: Antimicrobial Trimethylated Acylphloroglucinols from Ma̅nuka (<i>Leptospermum scoparium</i>)

Four trimethylated acylphloroglucinols (<b>5</b>–<b>8</b>) have been isolated from ma̅nuka (<i>Leptospermum scoparium</i>) foliage. Apart from myrigalone A (<b>8</b>), which has previously been isolated from European bog myrtle (<i>Myrica gale</i>), these compounds have not been characterized before. The nortriketones are structurally similar to the bioactive tetramethylated β-triketones from ma̅nuka, but have one less ring methyl group. Two oxidized trimethylated compounds, <b>9</b> and <b>10</b>, were also isolated, but these are likely isolation artifacts. When evaluated for antibacterial activity against Gram-positive bacteria, myrigalone A (<b>8</b>) was slightly less potent (MIC 64 μg/mL) than the corresponding tetramethylated compound, grandiflorone (<b>4</b>) (MIC 16–32 μg/mL). Unlike their tetramethylated analogues, the nortriketones were inactive against the herbicide target enzyme <i>p</i>-hydroxyphenylpyruvate dioxygenase. The Raman spectra of leaf oil glands in different ma̅nuka varieties can be used to distinguish plants that contain nortriketones from those that accumulate triketones

Mitochondrial rerouting of chlorambucil.

<p>(a) <b><i>Schematic of chlorambucil redirected to mitochondria.</i></b> Conjugation of chlorambucil (Cbl) to a mitochondria-penetrating peptide (MPP) sequence (mt-Cbl) redirects Cbl from its usual nuclear target to the mitochondrion. (b) <b><i>Chemical structure of mt-Cbl.</i></b> Cbl is conjugated to a MPP through the N-terminus.</p

<i>In vivo</i> profiles of mt-Cbl and Cbl.

<p>(a<i>) </i><b><i>Pharmacokinetic profile of mt-Cbl and Cbl.</i></b> 10 mg/kg of Cbl or mt-Cbl was administered to mice and plasma levels of both compounds were measured via HPLC-MS/MS. Mt-Cbl is eliminated more gradually than Cbl. Mean values plotted, n = 3, error bars are standard deviation. (b<i>) </i><b><i>Biodistribution of mt-Cbl and Cbl.</i></b> Both compounds show similar profiles suggesting that the MPP peptide does not alter distribution of Cbl. Mean values plotted, n = 3, error bars are standard deviation. (c) <b><i>Liver enzyme levels following treatment.</i></b> Mice were treated as above and their plasma was assessed for levels of bilirubin, alkaline phosphatase and aspartate transaminase. No significant increase was noted in any of the enzyme levels following treatment with Cbl or mt-Cbl. Mean values plotted, n = 4, error bars are s.e.m.</p

Pharmacokinetic parameters for mt-Cbl and Cbl.

<p>Pharmacokinetic parameters for mt-Cbl and Cbl.</p

Assessment of the role of protein damage in mt-Cbl cytotoxicity.

<p>(a) <b><i>Toxicity of mt-Cbl in a</i></b> ρ° <b><i>cell model.</i></b> After overnight incubation, mt-Cbl was more potent in the ρ° cell line indicating the importance of mt-Cbl's protein targets. (b) <b><i>Mt-Cbl and Cbl-TPP mitochondrial protein targets in vitro.</i></b> HL60 cells were treated with mt-Cbl-bt or Cbl-TPP and then mitochondrial lysates were immunoblotted. Lane 1: Control HL60 cells, Lane 2: Treated HL60 cells. (c) <b><i>Toxicity of Cbl-TPP in a</i></b> ρ ° <b><i>cell model.</i></b> Cbl-TPP toxicity profiles in 143B parental and its ρ° derivative overlap.</p