Design and synthesis of a photoaffinity labelling analogue of ivacaftor to probe its putative binding site on mutant CFTR

Date created: 
2017-03-06
Identifier: 
etd10034
Keywords: 
CFTR
Ivacaftor
Mechanism of action
Diazirine
Photoaffinity labelling
Synthesis
Abstract: 

The cystic fibrosis (CF) therapeutic, ivacaftor, restores activity to certain cystic fibrosis transmembrane regulating protein (CFTR) mutations; however, the nature of ivacaftor's interaction with mutant CFTR is still under investigation. This study aimed to generate photoaffinity labelling (PAL) probes that will be used to elucidate putative ivacaftor binding sites on mutant CFTR. Structure activity relationship studies indicated retention of ivacaftor's potentiating activity despite deletion of either of the t-butyl groups from the ivacaftor structure. These results initiated a synthesis program to prepare PAL probes incorporating a carbene-generating diazirine moiety in place of a t-butyl group on the ivacaftor scaffold. Initial synthetic approaches towards creating the diazirine PAL probe were devised with the ability to afford diversification at a late stage in the synthesis to allow incorporation of reporter tags into the PAL probe. While these approaches were unsuccessful, ultimately a linear synthetic approach successfully afforded the target diazirine PAL probe.

Document type: 
Thesis
Rights: 
This thesis may be printed or downloaded for non-commercial research and scholarly purposes. Copyright remains with the author.
Senior supervisor: 
Robert Young
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) M.Sc.
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