Lisa J. Whalen

Resolution of a chiral alcohol through lipase-catalyzed transesterification of its mixed carbonate by poly(ethylene glycol) in organic media

Abstract A simple approach to the resolution of chiral alcohols through a lipase-catalyzed transesterification of one enantiomer of the corresponding trifluoroethyl carbonate by a low molecular weight poly(ethylene glycol), PEG, is described. The method was demonstrated through resolution of ( RS )- sec -phenethyl alcohol. The alcohol was converted to its 2,2,2-trifluoroethyl carbonate, 2 , and the ( R )-enantiomer was selectively transesterified with PEG in warm diisopropyl ether using porcine pancreas lipase, PPL, as the catalyst. The two carbonate enantiomers were easily separated by cooling and filtering off the solid PEG having the ( R )-alcohol covalently attached. Hydrolysis of the unchanged ( S )-carbonate was achieved in dilute aqueous base, and the enantiomeric excess of the ( S )-alcohol was found to be 80% by NMR in the presence of the chiral shift reagent Eu(hfc) 3 . Methanolysis of the modified ( R )-PEG carbonate yielded ( R )- sec -phenethyl alcohol having enantiomeric excess=96% by NMR with Eu(hfc) 3 .

Activation of anti-oxidant Nrf2 signaling by enone analogues of curcumin

Inflammation and oxidative stress are common in many chronic diseases. Targeting signaling pathways that contribute to these conditions may have therapeutic potential. The transcription factor Nrf2 is a major regulator of phase II detoxification and anti-oxidant genes as well as anti-inflammatory and neuroprotective genes. Nrf2 is widespread in the CNS and is recognized as an important regulator of brain inflammation. The natural product curcumin exhibits numerous biological activities including ability to induce the expression of Nrf2-dependent phase II and anti-oxidant enzymes. Curcumin has been examined in a number of clinical studies with limited success, mainly owing to limited bioavailability and rapid metabolism. Enone analogues of curcumin were examined with an Nrf2 reporter assay to identify Nrf2 activators. Analogues were separated into groups with a 7-carbon dienone spacer, as found in curcumin; a 5-carbon enone spacer with and without a ring; and a 3-carbon enone spacer. Activators of Nrf2 were found in all three groups, many of which were more active than curcumin. Dose-response studies demonstrated that a range of substituents on the aromatic rings of these enones influenced not only the sensitivity to activation, reflected in EC50 values, but also the extent of activation, which suggests that multiple mechanisms are involved in the activation of Nrf2 by these analogues.