Lipophilicβ-Cyclodextrin Cyclic-Nitrone Conjugate: Synthesis and SpinTrapping Studies

摘要

Nitrone spin traps are commonly employed as probes for the identification of transient radicals in chemicaland biological systems using electron paramagnetic resonance (EPR) spectroscopy. Nitrones have alsofound applications as therapeutic agent in the treatment of radical-mediated diseases. Therefore, a spintrap that incorporates high reactivity to superoxide radical anion (O_2~-), more persistent superoxideadduct, enhanced bioavailability, and selective targeting in one molecular design is desirable. In this work,the synthesis of a nitrone spin trap, 4, that is tethered via amide bonds to a β-cyclodextrin (β-CD) and adodecyl chain was achieved with the expectation that the β-cyclodextrin would lead to increased reactivityto O_2~- and persistent O_2~- adduct while the lipophilic chain would impart membrane targeting property.The two constitutional racemic isomers, 4a and 4b, were separated using preparative HPLC, and structuralanalysis and self-aggregation properties were carried out using NMR, induced circular dichroism, dynamiclight scattering, transmission electron microscopy, and computational approach. EPR spin trapping ofO_2~-by4a and 4bwas only successful in DMSO not an aqueous system, due most likely to theamphiphilic character of 4 that can favor conformations (or aggregation) hindering radical addition tonitrone. Kinetics of formation and decay of the 4a-0_2Hadduct in polar aprotic solvents show fasterreactivity to O_2~-and more persistent O_2~- adduct compared to nitrones not conjugated β-CD.Computational analysis of 4a and 4b as well as 4a-00H and 4b-OOH adducts were carried out, and resultsshow that isomerism, both constitutional and stereochemical, affects the orientations of aminoxyl-NOand/or hydroperoxyl groups relative to the β-CD annulus for optimal H-bond interaction and stability.