Alpha-methylene-gamma-butyrolactones: versatile skin bioactive natural products.
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.
Lepoittevin
Jean-Pierre
JP
Laboratoire de Dermatochimie, Institut de Chimie (UMR 7177 CNRS/UdS), Université de Strasbourg, 67070 Strasbourg, France. jplepoit@unistra.fr
Berl
Valérie
V
Giménez-Arnau
Elena
E
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use; D001688:Biological Products / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology; D017449:Dermatitis, Allergic Contact; D010936:Plant Extracts / Q000009:adverse effects / Q000032:analysis / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism
D001688:Biological Products; D010936:Plant Extracts; C014096:alpha-methylene gamma-butyrolactone; D015107:4-Butyrolactone