Traditional approaches in pharmaceutical chemistry are facing a challenge as about 80 % of the human proteome is inaccessible with traditional small-molecule approaches, which limits their applicability in many diseases. Therefore, there is a need for novel approaches and medicinal chemistry modalities, such as targeted protein degradation with proteolysis-targeting chimeras (PROTACs).
PROTACs are compounds that rely on the event-driven pharmacology model as they induce proteolytic degradation of target proteins by hijacking the naturally occurring ubiquitin-proteasome system. This approach has already shown a number of advantages, such as catalytic mode of action. Namely, after successful degradation of the targeted protein, PROTAC can undergo several cycles of ternary complex formation and protein degradation. PROTACs are effective at sub-stoichiometric quantities which results in lower concentrations needed for physiological effect. This fact translates to a lower risk of side effects. PROTACs also have a longer lasting pharmacodynamic effect due to the degradation of the target, rather than merely inhibiting it. They can also bind to any pocket of the protein, thus increasing the number of pharmacologically relevant targets that can be tackled with this methodology. PROTACs are composed of three elements: a ligand that binds to the target protein, a ligand for the selected ubiquitin ligase E3 and a linker that connects the two moieties. Most PROTACs are based on Von Hippel-Lindau (VHL) E3 ligase, cereblon (CRBN), inhibitor of apoptosis (IAP), and mouse double minute 2 homologue (MDM2).
In this master's thesis we attempted to optimize the previously described synthetic pathway of two ligands for VHL as the development of an efficient synthesis process is an important step not only for further development of PROTACs but also for their potential industrial utility. In addition to simplification and yield increase, the primary purpose of the synthesis of the first ligand was also the preparation of multigram quantities of the benzylamine building block, which is a very useful precursor in the synthesis of VHL ligands. The optimized synthesis of first ligand was then applied to the second ligand, which is structurally similar, but has a higher affinity for VHL. Optimization was successful in the synthesis of first ligand, as in the part of the reaction that represented the greatest problem, the yield was improved from 28 % to 41 %. Furthermore, applying optimized linear synthesis to the synthesis of structurally similar ligand showed comparable yields to described convergent synthesis, thus further showcasing the importance of our work.
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