RESUMEN
Here we report the design of a general, redox-switchable organophosphorus alkyl radical trap that enables the synthesis of a broad range of C(sp3)-P(V) modalities. This "plug-and-play" approach relies upon in situ activation of alcohols and OâP(R2)H motifs, two broadly available and inexpensive sources of molecular complexity. The mild, photocatalytic deoxygenative strategy described herein allows for the direct conversion of sugars, nucleosides, and complex pharmaceutical architectures to their organophosphorus analogs. This includes the facile incorporation of medicinally relevant phosphonate ester prodrugs.
RESUMEN
AIMS: There are reports that ataxia telangiectasia mutated (ATM) can activate the AMP-activated protein kinase (AMPK) and also Akt, two kinases that play integral parts in cardioprotection and metabolic function. We hypothesized that chloroquine and resveratrol, both known ATM activators, would also activate AMPK and Akt. MAIN METHODS: Phosphorylation of AMPK and Akt was assessed after C2C12 myotubes were exposed to chloroquine or resveratrol. Additional experiments were done in cells expressing shRNA against ATM or in the presence of the ATM inhibitor KU55933. The effects of chloroquine on intracellular calcium were assessed with the fluorescent probe Calcium Green-1 AM. KEY FINDINGS: 0.5 mM chloroquine increased AMPK phosphorylation by nearly 4-fold (P<0.05), and 0.25 mM chloroquine roughly doubled Akt phosphorylation (P<0.05). Chloroquine also increased autophosphorylation of ATM by ~50% (P<0.05). Resveratrol (0.15 mM) increased AMPK phosphorylation about three-fold (P<0.05) but in contrast to chloroquine sharply decreased Akt phosphorylation. Chloroquine increased AMPK and Akt phosphorylation in myotubes expressing shRNA against ATM that reduced ATM protein levels by about 90%. Likewise, chloroquine-stimulated phosphorylation of AMPK and Akt and resveratrol-stimulated phosphorylation of AMPK were not altered by inhibition of ATM. Chloroquine decreased intracellular calcium by >50% concomitant with a decrease in glucose transport. SIGNIFICANCE: These ATM-independent effects of chloroquine on AMPK and Akt and the additional effect to decrease intracellular calcium are likely to partially underlie the positive metabolic effects of chloroquine that have been reported in the literature.