Synthesis of fluorinated analogs of KRN7000

Identifier:  TDX:2668

Handle: https://hdl.handle.net/20.500.11797/TDX2668

Authors:  Collado Fernández, David

Abstract:
KRN7000 (α-GalCer) is a synthetic glycosphingolipid which exhibits potent anti-tumor activity by stimulating a strong immune response. The KRN7000 biochemical mechanism for such therapeutical effect goes through the formation of a ternary complex between CD1d protein, KRN7000 and TCR receptor of NKTcells. Upon complexation, different types of cytokines are released promoting different biological responses. It is believed that both the potency and the nature of the final biological outcome depend on the strength of the interactions between the components of the ternary complex. In this sense, it has been recently demonstrated that perfluorinated chains produce stronger interactions with proteins than its hydrocarbon counterparts, due to their higher hydrophobicity. Within this context, the research described in this thesis aims to investigate the synthesis of KRN7000 analogues in which lipid hydrocarbon chains are replaced by fluoroalkyl ones in order to determine the biological outcome of such structural modification. For this purpose, different fluoroalkylation methods have been tested leading to the successful preparation of a battery of KRN7000 analogues differing on both the position of fluoroalkyl chains and the compound fluorination degree. In addition, during the development of this thesis, an additional objective aroused: the synthesis of coformationally restricted KRN7000 analogues. Preliminar biological evaluation of the synthesized analogues is also presented herein evidencing the high impact of H/F replacement on the compound activity. In addition, molecular dynamic studies have been performed, providing useful information for the understanding, at a molecular level, of the behaviour of the fluoroalkyl chains in the biological system.