Lipophilic β-cyclodextrin cyclic-nitrone conjugate: Synthesis and spin trapping studies

Yongbin Han, Yangping Liu, Antal Rockenbauer, Jay L. Zweier, Grégory Durand, Frederick A. Villamena

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

(Figure Presented) 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 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 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 O 2•- 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.

Original languageEnglish
Pages (from-to)5369-5380
Number of pages12
JournalJournal of Organic Chemistry
Volume74
Issue number15
DOIs
Publication statusPublished - Aug 7 2009

ASJC Scopus subject areas

  • Organic Chemistry

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