title: Structure-activity relationships for contact allergenic potential of gamma,gamma-dimethyl-gamma-butyrolactone derivatives. 1. Synthesis and electrophilic reactivity studies of alpha-(omega-substituted-alkyl)-gamma,gamma-dimethyl-gamma-butyrolacton es and correlation of skin sensitization potential and cross-sensitization patterns with structure.
abstract: A series of alpha-(X-substituted-methyl)-gamma,gamma-dimethyl-gamma-butyrolactones (series 1), a series of alpha-(2-X-substituted-ethyl)-gamma,gamma-dimethyl-gamma-butyrolactones (series 2), where X is a leaving group, and the compound alpha-(3-bromopropyl)-gamma,gamma-butyrolactone (3) were synthesized. Their reactions as electrophiles toward n-butylamine, used as a model for nucleophilic groups on skin proteins whose in vivo chemical modification leads to skin sensitization, were investigated. The compounds of series 1 were shown to react via a two-stage elimination--Michael addition sequence whereby the elements of HX are eliminated to form alpha-methylene-gamma,gamma-dimethyl-gamma-butyrolactone, which reacts more slowly with n-butylamine to give alpha-[(N-butylamino)methyl]-gamma,gamma-dimethyl-gamma-butyrolactone. The compounds of series 2 and compound 3 were shown to react with n-butylamine via a single-stage substitution reaction to give respectively alpha-[2-(N-butylamino)ethyl]- and alpha-[3-(N-butylamino)propyl]-gamma,gamma-dimethyl-gamma-butyrolactones . Rate constants for these reactions have been determined, and it is found that substitution reactions of series 2 and compound 3 are slower than Michael addition of alpha-methylene-gamma,gamma-dimethyl-gamma-butyrolactone, which in turn is slower than the elimination reactions of series 1. The results of guinea pig skin sensitization tests on these compounds were found to be consistent with the above findings in that the compounds of series 1 were found to be in general much stronger sensitizers than those of series 2 and compound 3. The results of cross-challenge tests indicate that sensitizing compounds from series 2 were cross-reactive with both series 1 and compound 3 but that compound 3 is only weakly cross-reactive with series 1. These observations indicated that for these compounds a difference of two carbon atoms between the determinant groups transferred to protein had a markedly greater effect than a difference of one carbon atom on antigenic specificity.
authors.affiliation: Laboratoire de Dermatochimie associé au CNRS, Université Louis Pasteur, CHU, Strasbourg, France.
authors.forename: C
authors.initials: C
authors.lastname: Franot
authors.forename: D W
authors.initials: DW
authors.lastname: Roberts
authors.forename: R G
authors.initials: RG
authors.lastname: Smith
authors.forename: D A
authors.initials: DA
authors.lastname: Basketter
authors.forename: C
authors.initials: C
authors.lastname: Benezra
authors.forename: J P
authors.initials: JP
authors.lastname: Lepoittevin
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000485:Allergens / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000918:Antibody Specificity; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003429:Cross Reactions; D017449:Dermatitis, Allergic Contact / Q000503:physiopathology*; D006168:Guinea Pigs; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D012882:Skin Tests; D013329:Structure-Activity Relationship
chemical_list: D000485:Allergens; D015107:4-Butyrolactone