This thesis describes the synthesis and biological evaluation of TLR2/6, TLR4, TLR7/8 and TLR9 ligands, of which the activity can be conditionally controlled. Trans-cyclooctenes are used to shield... Show moreThis thesis describes the synthesis and biological evaluation of TLR2/6, TLR4, TLR7/8 and TLR9 ligands, of which the activity can be conditionally controlled. Trans-cyclooctenes are used to shield the ligand's moiety critical for TLR activation, which can be removed fast and quantitatively by the addition of tetrazine derivatives. Photocages are used in parallel for the same purpose, which can be removed by exposure to low-energetic UV-light. A new photocage has been developed that can be decorated on two positions, i.e. it is bifunctional. This photocage has been used to synthesize a proteasome inhibitor-doxorubicin conjugate, in which the photocage bisects the two groups, which induces apoptosis in targeted multiple myeloma cells with an acquired resistance for proteasome inhibitors. The photocage was also used to synthesize a probe that enables targeting and isolation of CD8+ T cells in viable human melanoma and non-squamous cell lung cancer tissues. Show less
The inverse electron demand Diels-Alder (IEDDA) pyridazine elimination emerged in 2013 as a new bioorthogonal reaction and constitutes a prime example of what is now known as dissociative... Show moreThe inverse electron demand Diels-Alder (IEDDA) pyridazine elimination emerged in 2013 as a new bioorthogonal reaction and constitutes a prime example of what is now known as dissociative bioorthogonal chemistry. The research described in this Thesis aims to develop synthetic strategies which enable the IEDDA pyridazine elimination to be applied as a versatile toolbox in chemical biology studies. More specifically, it entails modification of antigenic (MHC-I) peptides and (CD1d) glycolipids with a trans-cyclooctene (TCO) moiety to allow chemical control over the recognition of these biomolecules by immune cells. Synthetic advances which encompass the entire scope of the IEDDA pyridazine elimination are additionally described. Show less
