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

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.

journal_name

Chem Res Toxicol

authors

Franot C,Roberts DW,Smith RG,Basketter DA,Benezra C,Lepoittevin JP

doi

10.1021/tx00039a005

subject

Has Abstract

pub_date

1994-05-01 00:00:00

pages

297-306

issue

3

eissn

0893-228X

issn

1520-5010

journal_volume

7

pub_type

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