Cancer is lacking early detection methods and treatment specificity. In order to increase the sensitivity and specificity towards cancer cells, we propose the use of multivalent interactions targeting specific receptor combinations at the cancer cell surface. In this thesis, we explored the design of multimers, which could provide such interactions. The design was investigated and revisited based on specific parameters, essential for the creation of multivalent interactions such as thermodynamics. The synthesis was designed so that libraries of homo- and hetero-multimers of different valencies can be obtained efficiently with good yields. The established synthetic scheme is empowered by its modularity, necessary to investigate different essential factors. Trimers composed of micromolar affinity MSH(4) targeting the MC1-R, overexpressed in melanoma, were investigated on a model cell line and resulted in the creation of nanomolar affinity constructs with up to 350 fold increase in affinity. Different multimers such as hexavalent and nonavalent dendrimers were synthesized and studied for their properties. All constructs had nanomolar affinity and showed to be non-toxic up to micromolar concentrations and imaging studies also confirmed their internalization, which overall demonstrate the potential for these compounds to be used as markers for cancer cells and as delivery agents. Trimers targeting the CCK2-R were similarly investigated for their potential as pancreatic cancer markers. However, those constructs did not seem to result in the expected enhancements in affinity, but the affinity of the initial monovalent agonist was in the 10-50 nanomolar range. As we were unable to design micromolar affinity agonist we investigated the use of antagonists. This study, revealed the importance of thermodynamics in the creation of multivalent interaction. Heterotrivalent ligands (CCK and MSH) were investigated for their potential in cross-linking different receptors and the study demonstrated the subtility to detect cross-linking. Finally, the different attempts toward the efficient synthesis of a tetra-orthogonal scaffold, a key feature needed to generate multimers that could target up to 3 different receptors was investigated and showed promising results. It is our hypothesis that such an approach will ultimately lead to specific markers of tumor cells, which could be used as diagnosis agents when modified with an imaging moiety and as a therapeutic agent when modified with a drug.

In the adaptation to the oxidative environment on earth, metals played a crucial role for the evolution of life. The presence of metals also allowed access to advanced functions due to their unique coordination sphere and reactivity. This thesis focused on exploiting these unique properties for further development of the field of dynamic chemistry – a field in which adaptation plays a central role as well. The first part of the thesis aimed to create a better understanding of multivalent effects in carbohydrate-lectin interactions. By reversible ligand coordination to zinc ions one of the nanoplatforms, the Borromean rings, could be selectively obtained. After carbohydrate functionalization the binding events were monitored by quartz crystal microbalance technology and compared to glycosylated fullerenes and dodecaamide cages. Overall, this investigation indicated that statistical and polyelectrolyte effects play a considerable role in the observed multivalent effects. The second part of the thesis aimed to design and synthesize a new catalyst for application in aqueous olefin metathesis. This afforded a ruthenium based catalyst that was applied in the self- and cross-metathesis of highly functionalized substrates, such as carbohydrates. In addition, it was shown that addition of a small amount of acetic acid prevented undesired double bond isomerization. The last part of the thesis aimed to explore new methods to discover transition metal catalysts. Dynamic exchange of directing groups generated a pool of potential substrates for C-H activation. Combining this pool of substrates with a pool of potential catalysts resulted in amplification of a reactive substrate/metal combination. By iterative deconvolution in combination with mass spectrometry, this “intermediate” could be identified from the mixture, proving applicability of this alternative approach to catalyst discovery. / <p>QC 20170809</p>