Natural products containing an
alpha-methylene-gamma-butyrolactone moiety, mainly of the
sesquiterpene type, are widely observed in plants, which upon coming into contact with skin, will induce major skin toxicological side effects or phytodermatitis. Indeed two main dermatological pathologies have been associated with a skin exposure to molecules containing an
alpha-methylene-gamma-butyrolactone moiety:
allergic contact dermatitis (ACD) and
chronic actinic dermatitis (CAD). ACD is an immunologically based disease resulting from modifications of epidermal
proteins by sensitizers or
haptens. Indeed, alpha-methylene-gamma-butyrolactones are highly electrophilic structures that can act as Michael acceptors towards nucleophilic residues of
proteins.
Cysteine and
lysine are the most modified residues leading, in the case of enantiomerically pure
lactones, to the formation of diastereomeric adducts. This chemical enantioselectivity induces an enantiospecificity of the
allergic reaction, i.e., an individual sensitized to one enantiomer will not develop clinical symptoms when exposed to the other enantiomer and vice versa.
Sesquiterpene lactones have been also associated with another pathology that involves UV irradiation and
DNA modifications. Interestingly, it was found that alpha-methylene-gamma-butyrolactones, in addition to their electrophilic properties, were highly photoreactive molecules able to react with
thymine/
thymidine to form [2 + 2] photoadducts in very high yields. In all cases a syn regioselectivity was observed, probably associated with the polarization of the exomethylenic bond. This high photoreactivity of alpha-methylene-gamma-butyrolactones towards
thymidine could be an explanation of the progressive evolution of
allergic contact dermatitis towards
chronic actinic dermatitis.