Bihaptens with 5- and 6-methyl-substituted alkylcatechols and methylene lactone functional groups: tools for hapten (allergen or tolerogen)-protein interaction studies.

In order to investigate hapten-protein interactions in vivo, potential skin sensitizers 1-3, with two different haptenic ends, (a) a catechol, a 5-methylcatechol, and a 6-methylcatechol respectively, and (b) an alpha-methylene-gamma-butyrolactone moiety, separated by a straight 10-carbon chain, have been prepared and used to sensitize guinea pigs. Related "monohapten lactones" 19-21, containing an electrophilic alpha-methylene-gamma-butyrolactone moiety connected to the protected catechol structures, and "monohapten catechols" 25-27, containing a reduced alpha-methyl-gamma-butyrolactone linked to the catechol, also have been prepared. Bihaptens 1 and 2 which were found to have very close biological activities appear to react with proteins through the catechol ring, indicating a low importance of the C-6 position in the binding of catechols with amino acids. In contrast, bihapten 3 was found to react through both the catechol and lactone ring. The influence of amino and thiol binding sites on the biological activity (allergy or tolerance) as well as the influence of the sensitizing method are discussed.