Improved spin trapping properties by beta-cyclodextrin-cyclic nitrone conjugate.
Spin trapping using a nitrone and electron paramagnetic resonance (EPR) spectroscopy is commonly employed in the identification of transient radicals in chemical and biological systems. There has also been a growing interest in the pharmacological activity of nitrones, and there is, therefore, a pressing need to develop nitrones with improved spin trapping properties and controlled delivery in cellular systems. The beta-cyclodextrin (beta-CD)-cyclic nitrone conjugate, 5-N-beta-cyclodextrin-carboxamide-5-methyl-1-pyrroline N-oxide (CDNMPO) was synthesized and characterized. 1-D and 2-D NMR show two stereoisomeric forms (i.e., 5S- and 5R-) for CDNMPO. Spin trapping using CDNMPO shows distinctive EPR spectra for superoxide radical anion (O2(*-)) compared to other biologically relevant free radicals. Kinetic analysis of O2(*-) adduct formation and decay using singular value decomposition and pseudoinverse deconvolution methods gave an average bimolecular rate constant of k = 58 +/- 1 M(-1) s(-1) and a maximum half-life of t(1/2) = 27.5 min at pH 7.0. Molecular modeling was used to rationalize the long-range coupling between the nitrone and the beta-CD, as well as the stability of the O2(*-) adducts. This study demonstrates how a computational approach can aid in the design of spin traps with a relatively high rate of reactivity to O2(*-), and how beta-CD can improve adduct stability via intramolecular interaction with the O2(*-) adduct.
Han
Yongbin
Y
Department of Pharmacology, The Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA.
Tuccio
Beatrice
B
Lauricella
Robert
R
Villamena
Frederick A
FA
D003198:Computer Simulation; D003497:Cyclic N-Oxides / Q000138:chemical synthesis / Q000737:chemistry*; D004578:Electron Spin Resonance Spectroscopy / Q000379:methods; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy / Q000379:methods / Q000592:standards; D008956:Models, Chemical; D015394:Molecular Structure; D012015:Reference Standards; D019097:Spin Trapping / Q000379:methods*; D013237:Stereoisomerism; D013481:Superoxides / Q000032:analysis; D047392:beta-Cyclodextrins / Q000138:chemical synthesis* / Q000737:chemistry*
C532720:5-N-beta-cyclodextrin-carboxamide-5-methyl-1-pyrroline N-oxide; D003497:Cyclic N-Oxides; D047392:beta-Cyclodextrins; D013481:Superoxides; C031215:betadex