Lipophilic β-Cyclodextrin Cyclic−Nitrone Conjugate: Synthesis and Spin Trapping Studies

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• 作者：Yongbin Han ; Yangping Liu ; Antal Rockenbauer ; Jay L. Zweier ; Grgory Durand ; Frederick A. Villamena
• 刊名：Journal of Organic Chemistry
• 出版年：2009
• 出版时间：August 7, 2009
• 年：2009
• 卷：74
• 期：15
• 页码：5369-5380
• 全文大小：1102K
• 年卷期：v.74,no.15(August 7, 2009)
• ISSN：1520-6904

文摘

Nitrone spin traps are commonly employed as probes for the identification of transient radicals in chemical and biological systems using electron paramagnetic resonance (EPR) spectroscopy. Nitrones have also found applications as therapeutic agent in the treatment of radical-mediated diseases. Therefore, a spin trap that incorporates high reactivity to superoxide radical anion (O₂^•−), more persistent superoxide adduct, 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 a dodecyl chain was achieved with the expectation that the β-cyclodextrin would lead to increased reactivity to O₂^•− and persistent O₂^•− adduct while the lipophilic chain would impart membrane targeting property. The two constitutional racemic isomers, 4a and 4b, were separated using preparative HPLC, and structural analysis and self-aggregation properties were carried out using NMR, induced circular dichroism, dynamic light scattering, transmission electron microscopy, and computational approach. EPR spin trapping of O₂^•− by 4a and 4b was only successful in DMSO and not in an aqueous system, due most likely to the amphiphilic character of 4 that can favor conformations (or aggregation) hindering radical addition to nitrone. Kinetics of formation and decay of the 4a-O₂H adduct in polar aprotic solvents show faster reactivity to O₂^•− and more persistent O₂^•− adduct compared to nitrones not conjugated to β-CD. Computational analysis of 4a and 4b as well as 4a-OOH and 4b-OOH adducts were carried out, and results show that isomerism, both constitutional and stereochemical, affects the orientations of aminoxyl-NO and/or hydroperoxyl groups relative to the β-CD annulus for optimal H-bond interaction and stability.