Laboratoire de Dermatochimie, Institut de Chimie (UMR 7177 CNRS/UdS), Université de Strasbourg, 67070 Strasbourg, France.
Chem Rec. 2009;9(5):258-70. doi: 10.1002/tcr.200900013.
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.
天然产物中含有α-亚甲基-γ-丁内酯部分，主要为倍半萜类，广泛存在于植物中，当与皮肤接触时，会引起严重的皮肤毒理学副作用或植物性皮炎。事实上，有两种主要的皮肤病理学与分子中含有α-亚甲基-γ-丁内酯部分的皮肤暴露有关：过敏性接触性皮炎（ACD）和慢性光化性皮炎（CAD）。ACD 是一种免疫为基础的疾病，是由敏化剂或半抗原对表皮蛋白的修饰引起的。事实上，α-亚甲基-γ-丁内酯是高度亲电的结构，可以作为迈克尔受体与蛋白质的亲核残基反应。半胱氨酸和赖氨酸是最被修饰的残基，在对映体纯内酯的情况下，导致非对映异构体加合物的形成。这种化学对映选择性诱导了过敏反应的对映体特异性，即对一种对映体致敏的个体在暴露于另一种对映体时不会出现临床症状，反之亦然。倍半萜内酯也与另一种涉及紫外线照射和 DNA 修饰的病理学有关。有趣的是，人们发现α-亚甲基-γ-丁内酯除了具有亲电性外，还是高度光反应性的分子，能够与胸腺嘧啶/胸苷形成[2+2]光加合物，产率非常高。在所有情况下，都观察到顺式区域选择性，可能与 exomethylenic 键的极化有关。α-亚甲基-γ-丁内酯对胸苷的高光反应性可能解释了过敏性接触性皮炎向慢性光化性皮炎的逐渐演变。
