CyDEPMPOs: A class of stable cyclic DEPMPO derivatives with improved properties as mechanistic markers of stereoselective hydroxyl radical adduct formation in biological systems
Résumé
The cis/trans diastereoisomeric composition of hydroxyl radical adducts to chiral cyclic nitrones can be
used to approach mechanisms of free radical formation in biological systems. Such determination is
greatly simplified when both diastereoisomers have ESR spectra with at least two non-overlapping lines.
To achieve this prerequisite, a series of DEPMPO-derived spin traps bearing one unsubstituted or alkylsubstituted
2-oxo-1,3,2-dioxaphosphorinane ring were synthesized and their structures were confirmed
by X-ray diffraction, 1H, 13C and 31P NMR. These CyDEPMPOs nitrones showed variable lipophilicities and
LD50 values on murine fibroblasts compatible with a safe use in biological spin trapping. All CyDEPMPOs
formed persistent spin adducts with a series of free radicals, including superoxide and hydroxyl (i.e.,
CyDEPMPOs-OH) and the in vitro half-life times of these two latter were at least as extended as those
of parent DEPMPO. Using four methods of CyDEPMPOs-OH formation, the cis-CyDEPMPOs-OH percentage
was found significantly varied with substitution on the P-containing ring and, more interestingly, with
the generating system.