α‐methylene‐γ‐butyrolactones: versatile skin bioactive natural products

Abstract

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.

Allergic contact dermatitis caused by topical herbal remedies: importance of patch testing with the patients' own products

“…Initial contact sensitization to SL may indeed lead to generalized photosensitivity , and Lepoittevin et al. showed photoreactivity of these molecules . Unfortunately, we did not photopatch test with the SL mix.…”

Unexpected positive patch test reactions to sesquiterpene lactones in patients sensitized to the glucose sensor FreeStyle Libre

“…Some SLs are characterized by an α‐methylene‐γ‐butyrolactone ring (Figure ). Such structures and, notably, the α,β‐unsaturated carbonyl chemical functional group have been shown to be good electrophiles that undergo covalent binding with nucleophilic residues of skin proteins via 1,4‐addition or Michael addition, which is responsible for their sensitizing potential …”

“…IBOA, and alantolactone, costunolide, and dehydrocostus, the three lactones present in SLM, share the same chemically reactive functional group. Indeed, these molecules contain a carbonyl functional group (double bond between a carbon and an oxygen atom), and are able to induce a Michael addition; this reaction represents the addition of a nucleophile to an α,β‐unsaturated carbonyl compound, acting as a Michael acceptor with a skin protein, or an amino acid responsible for the protein activity, such as cysteine . However, during the elicitation phase, two factors are crucial, that is, the function of the chemical groups and the three‐dimensional structure.…”

“…Such structures and, notably, the α,β-unsaturated carbonyl chemical functional group have been shown to be good electrophiles that undergo covalent binding with nucleophilic residues of skin proteins via 1,4-addition or Michael addition, which is responsible for their sensitizing potential. 7,8 SLM was developed for patch testing, and is estimated to detect 60% to 70% of all Compositae contact allergies 9 ; it is therefore included in the European baseline series. 10 Interestingly, within a country, significant differences between the percentages of simultaneous reactions to SLM and Compositae mix can be observed.…”

Sesquiterpene lactones as drugs with multiple targets in cancer treatment

“…Some SLs are active ingredients in many traditional herbal medicines as well as in modern phytotherapeutic drugs, notably Artemisia, Arnica, Ambrosia, Helenium, Tanacetum, and Vernonia spp. However, these SLs can also be cytotoxic or neurotoxic [11], and have often been reported as a cause of allergic contact dermatitis [12,13]. However, these SLs can also be cytotoxic or neurotoxic [11], and have often been reported as a cause of allergic contact dermatitis [12,13].…”