Nitrones/"spin traps" as "next-gen antioxidants" to proactively neutralize free radicals before they damage

The best known spin trap is PBN (Phenyl t-Butylnitrone), also called “Nitrone”.

According to Sawant,2 there are five primary spin traps of interest for health and skin conditions, based on safety considerations. These include: two nitrones, i.e., the aforementioned phenyl-N-tert butyl nitrone and 5,5-dimethyl-1-pyrroline N-oxide; plus, four nitroxides; and a hydroxylamine-TEMPO. To reduce inflammation in chronic diseases, 5,5-dimethyl-1-pyrroline N-oxide (DMPO) shows promise as the foundation for future anti-inflammatory drugs.3, 4 And phenyl-N-tert butyl nitrone appears to protect the central nervous system; especially the brain, which is very susceptible to oxidative damage.5

On a fundamental level, spin traps are like next-gen antioxidants. They make a proactive strike against free radicals by disarming and stabilizing them before they can cause damage. Antioxidants, on the other hand, while effective, are more reactive in nature, responding after the attack.

Several studies showed that PBN-type nitrones combine anti-inflammatory, antioxidant, and neuroprotective properties and are able to cross the blood–brain barrier. [(19,20)](javascript:void(0):wink: These nitrones could therefore be used for the treatment of stroke, [(21)](javascript:void(0):wink: visual loss, [(22,23)](javascript:void(0):wink: neuronal damage, [(24)](javascript:void(0):wink: and other age-related diseases. [(25)](javascript:void(0):wink: The PBN derivative called 2,4-disulfophenyl-N-tert-butyl nitrone (NXY-059) was the first neuroprotective agent to reach phase III clinical trials in the United States. [(26,27)](javascript:void(0):wink:

Nitrones have a very broad activity that depends on the nature and the position of the substituents on the nitronyl function. Therefore, the choice of substituents is very important and depends on the properties to be improved such as water solubility, [(28,29)](javascript:void(0):wink: lipophilicity, [(29,30)](javascript:void(0):wink: rate constant of radical trapping, [(31−33)](javascript:void(0):wink: adduct stability, [(34)](javascript:void(0):wink: bioactivity, [(23,35)](javascript:void(0):wink: and the possibility of cellular or tissue targeting thanks to the ligation to specific molecular targets. [(36−41)](javascript:void(0):wink: Over the past several years, the reactivity of the para-substituted derivatives of PBN has been explored to identify the most promising substituent for improved and optimal reactivity toward free radicals. It has been shown that the electronic nature of the substituent influences the rate of radical trapping on the nitronyl function. The presence of an electron-withdrawing group on the para position of the phenyl ring increased the reactivity toward nucleophilic addition reactions. [(31−33,42)](javascript:void(0):wink: Contrarily, nitrones with an electron-donating group exhibited high reactivity toward electrophilic radicals. [(43,44)](javascript:void(0):wink: The polar effect of the substituents has also been correlated with the electrochemical properties of the nitronyl function, with the derivatives bearing an electron-withdrawing group easier to reduce and harder to oxidize than those bearing an electron-donating group. [(33)](javascript:void(0):wink: