Tunable Delocalization of Unpaired Electrons of Nitroxide Radicals for Sickle-Cell Disease Drug Improvements

Hydroxyurea is a drug recently approved to treat sickle cell diseases. Hydroxyurea benefits the patients by increasing the level of fetal hemoglobin via a nitroxide radical pathway. Here, we report an unpaired-electron-delocalization approach to tune the stability of nitroxide radicals. In this approach, the substitution by an unsaturated alkyl group containing conjugated CC double bonds for the hydrogen on the nitrogen atom attached to the hydroxyl of hydroxyurea can significantly increase its ability to generate nitroxide radical. Furthermore, the increase can be remarkably enhanced by increasing the number of conjugated CC double bonds. For a hydroxyurea derivative that contains two conjugated CC double bonds, the reaction rate to generate its radical is 118 times faster than that of hydroxyurea, and for a hydroxyurea derivative containing 20 conjugated CC double bonds, the reaction rate to form its radical is 238 times faster than that of hydroxyurea. For this reason, hydroxyurea derivatives with conjugated CC double bonds may constitute new potential drugs for the treatment of sickle-cell diseases.