Lipophilic beta-cyclodextrin cyclic-nitrone conjugate: synthesis and spin trapping studies

Area of Science:

• Chemical Biology
• Spectroscopy
• Medicinal Chemistry

Background:

• Nitrone spin traps are crucial for detecting transient radicals in chemical and biological systems via electron paramagnetic resonance (EPR) spectroscopy.
• Nitrone derivatives are explored for treating radical-mediated diseases, highlighting the need for improved spin trap properties.

Purpose of the Study:

• To design and synthesize a novel nitrone spin trap conjugated to beta-cyclodextrin (beta-CD) and a dodecyl chain.
• To enhance reactivity towards superoxide radical anion (O2(*-)), improve adduct persistence, and impart membrane targeting capabilities.
• To investigate the influence of constitutional and stereochemical isomerism on the spin trap's properties and radical adduct stability.

Main Methods:

• Synthesis of nitrone spin trap 4, tethered to beta-cyclodextrin and a dodecyl chain.
• Separation of racemic isomers (4a and 4b) using preparative High-Performance Liquid Chromatography (HPLC).
• Characterization using Nuclear Magnetic Resonance (NMR), induced circular dichroism, dynamic light scattering, transmission electron microscopy, and computational analysis.
• Electron paramagnetic resonance (EPR) spin trapping experiments to study O2(*-) reactivity and adduct stability in various solvents.

Main Results:

• The synthesized nitrone spin traps (4a and 4b) exhibited increased reactivity and persistence towards O2(*-) in polar aprotic solvents compared to unconjugated nitrones.
• EPR spin trapping of O2(*-) was successful in DMSO but not in aqueous systems, likely due to the amphiphilic nature of the molecule hindering radical addition.
• Computational analysis revealed that isomerism significantly impacts the orientation of functional groups, influencing hydrogen bonding and stability of the radical adducts.

Conclusions:

• The beta-cyclodextrin conjugation enhances the reactivity and persistence of nitrone spin traps towards superoxide radicals in specific solvent systems.
• The amphiphilic nature of the designed spin traps presents challenges for application in aqueous biological environments.
• Isomerism plays a critical role in the molecular interactions and stability of these novel spin trap conjugates.