Synthesis of chemical tools to study the immune system

Graaff, M.J. van de (2023)

Doctoral Thesis

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 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.

• Chemocage
• Photocage
• Trans-cyclooctene
• Uncaging
• Spatiotemporal control
• TLR ligands
• Bifunctional

• All authors: Graaff, M.J. van de
• Supervisor: Kasteren, S.I. van; Overkleeft, H.S.
• Committee: Codee, J.D.C.; Stelt, M. van de; Filippov, D.V.; Hoogendoorn, S.; Brunsveld, L.
• Qualification: Doctor (dr.)
• Awarding Institution: Leiden Institute of Chemistry (LIC), Faculty of Science, Leiden University
• Date: 2023-01-19
• ISBN (print): 9789464588217