University of Groningen
Development of Novel Covalent Inhibitors and Other Scaffolds Through Multicomponent
Reactions
Sutanto, Fandi
DOI:
10.33612/diss.133643092
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Publication date: 2020
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
Sutanto, F. (2020). Development of Novel Covalent Inhibitors and Other Scaffolds Through Multicomponent Reactions. University of Groningen. https://doi.org/10.33612/diss.133643092
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SUMMARY AND FUTURE PERSPECTIVES
The aim of this dissertation is to provide the application of MCRs in the discovery of covalent inhibitors and other aspects in drug discovery.
In chapter 1, we discuss the growth of covalent inhibitors, which started in late 18th century,
received a lot of skepticism due to their reactivity and toxicity, and ended up being a majority of drugs with more than 50 approved covalent inhibitors on the market. One of the newest covalent inhibitors is also currently in a clinical trial, targeting RAS, which was considered an undruggable target. Noteworthy, a PROTAC originating from the combination of covalent inhibitor and ligand targeting E3 ligases VH032 is reported to show excellent results regarding BTK degradation. In chapter 2 and 3, we present the utilization of MCRs in the establishment of covalent inhibitors. Through many different electrophilic building blocks and MCR scaffolds, we synthesized more than one hundred of covalent inhibitors. We also performed high-throughput synthesis on a nanoscale in an automated fashion to produce libraries of potential covalent inhibitors in a resource- and time-saving way.
Fig. 1. A comparison between classic chemistry and MCR in the syntheses of covalent inhibitors.
Chapter 4 describes the synthesis of 1-tetrazolyl-imidazo[1,5-α]pyridine derivatives via
Azido-Ugi-deprotection, followed by acetic anhydride mediated N-acylation-cyclization. The synthetic method through MCR is novel, simple, and efficient compared to existing method.
Fig. 2. The MCR synthetic route towards 1-tetrazolyl-imidazo[1,5-α]pyridine derivatives.
SUMMARY AND FUTURE PERSPECTIVES
In chapter 5, we discuss the scaffold of 2-(imidazo[1,5-α]pyridin-1-yl)-1,3,4-oxadiazole, a bis-heterocycle which its biological importance is known. However, the synthetic route to access the scaffold is lengthy and time-consuming. It requires six steps and several purifications to obtain the final product. Through MCR, we synthesized the scaffold in three steps and single purification at the end to afford the final product. This method would allow the acceleration of biological evaluation of this scaffold.
Fig. 3. The MCR synthetic route towards 2-(imidazo[1,5-α]pyridin-1-yl)-1,3,4-oxadiazole derivatives.
In chapter 6, we present the combination of computational chemistry and MCR chemistry to develop aspartic protease inhibitors. A docking protocol was developed to obtain virtual libraries, followed by a virtual screening and synthesis of a series of Ugi-tetrazole derivatives was synthesized based on the results. The biological screening, together with the obtained co-crystal structures show the fascinating synergy between computational and laboratory chemistry.
Overall, this thesis shows that MCR is an advanced instrument for drug design. Application of MCR is proven to shorten the time of traditional synthetic routes, expand the diversity of starting materials, and the variety of products. The use of MCR in medicinal chemistry gives fast access to a big diversity of compounds accelerating the drug discovery process and improving cost efficiency, also applying the automated approach. Thus, MCR is a powerful tool in the process of drug discovery, which is giving advantages in comparison with traditional methods of organic synthesis.
