Structure-activity relationships in the murine local lymph node assay for skin sensitization: alpha,beta-diketones

The biological activity of skin-sensitizing chemicals is related to their a bility to react, either directly or after metabolic activation, with approp riate skin proteins. For direct acting electrophilic compounds, this abilit y can be modelled, using the RAI (relative alkylation index) approach, by a combination of electrophilicity and hydrophobicity parameters. Several str ucture-activity relationships based on this approach have been reported, bu t most of them cover guinea pig sensitization test data on what chemists wo uld classify as relatively soft electrophilic chemicals. In the present wor k, an electrophilicity parameter based on Taft substituent constants is der ived for hard electrophiles having a reactive carbonyl group, and is used t o calculate RAI values for the analyis of sensitization test data obtained in the murine local lymph node assay (LLNA) for a series of alpha,beta-dike tones. The sensitization potential of these reactive hard electrophilic car bonyl compounds in the LLNA shows a good correlation with the RAI. Overall, the findings reaffirm our view that physical organic chemistry is the key to understanding why some chemicals sensitize more strongly than others, wh ile some do not sensitize at all, and provide further evidence of the value of the LLNA for SAR studies.