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Title: Structure-activity relationships for the allergenic potential of diketones
Author: Gutsell, S. J.
ISNI:       0000 0004 2678 3162
Awarding Body: University of Wales Swansea
Current Institution: Swansea University
Date of Award: 2005
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Dicarbonyl compounds have been implicated in the process of skin sensitisation. It is widely accepted that the mechanism involved in this allergic reaction relies upon the reactions of these electrophilic compounds with the amino acid side chains of cellular proteins. The most likely points of reaction for dicarbonyl compounds are the side chains of the amino acids lysine and arginine. As such, model compounds were selected to mimic these nucleophilic groups. Butylamine was chosen to represent the lysine side chain. A series of mono- and di-alkylguanidine compounds were synthesised and their reactions with dicarbonyl compounds were evaluated. This led to butylguanidine being selected to mimic the arginine side chain. A series of 1,2- and 1,3-dicarboxyl compounds was selected which included some compounds for which biological data was available. Additional compounds were included in the series to investigate the effects of substituents on the carbonyl group. The majority of the 1,3-dicarbonyl compounds had to be synthesised. The reactions of these compounds towards the model nucleophiles were investigated and kinetic parameters were obtained. Reactions were monitored by HPLC. As part of the method development a study in to the effects of temperature and pH on the separation of 1,3-dicarbonyl compounds was undertaken. A short molecular modelling study was undertaken to investigate the dicarbonyl compounds. The parameters obtained were compared to the experimental orders of reactivity observed from the kinetic studies. Biological data was obtained for the additional compounds in the series. Both the kinetic and the computational parameters were then compared with this biological data. By using (Q)SAR approaches it was possible to identify correlations in the data and in the case of the 1,3-dicarbonyl compounds to develop a predictive model. This study also highlighted a possible structural alert associated with increased allergenic potency that could be used in rule-based prediction systems.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available