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Overcoming the Selectivity Challenge in Chemistry and Chemical Biology via Innovative Tethering Strategies

Periodic Reporting for period 2 - SeleCHEM (Overcoming the Selectivity Challenge in Chemistry and Chemical Biology via Innovative Tethering Strategies)

Berichtszeitraum: 2020-07-01 bis 2021-12-31

In the last two centuries, synthetic organic chemistry has undergone an unprecedented revolution. The ability to understand and modify the molecular structure of matter has changed our life in many areas, such as medicine, agriculture or commodity materials. These major successes gave the impression that synthetic chemistry is a mature field. However, this impression is completely misleading, as current synthetic methods still lack the selectivity needed for the modification of complex molecules. Both selecting between different reactive groups and functionalizing inert bonds in their presence represent formidable challenges. Nevertheless, we need to solve this challenge if we want to discover better drugs, agrochemicals and materials.
In this project, we propose to develop highly selective “molecular tethers” for the functionalization of both natural/synthetic organic compounds and biomolecules. The envisioned tethers are bifunctional small organic molecules having three fundamental properties:
1) A selective “biting end”, which is able to react with only one position, even on complex molecules.
2) A “functional end”, whose reactivity can be revealed “at will” to bring modification.
3) Being traceless, meaning that they can be removed easily once the desired functionalization has been achieved.

The main impact of this project will be in fundamental synthetic organic chemistry, as it will contribute to overcoming major selectivity hurdles in the functionalization of complex molecules. It will therefore result in faster progress in all the fields depending on synthetic molecules, such as medicine, agriculture or materials. A more efficient functionalization of biomolecules will allow us to soften the boundaries between synthetic chemistry and biology, leading to major progress in our understanding of living systems and our ability to modify them.
Since the beginning of the project, important results have already been obtained in two areas:

1) The selective functionalization of alkynes (carbon carbon triple bonds) using commercially available tethering molecules and a palladium catalyst. This reaction gives access to amino alcohols, essential structural elements, especially for medicinal chemistry. Indeed, more than 300'000 amino alcohols have already been reported. They can be found in more than 2000 natural products and 80 FDA approved drugs. The selective synthesis of such essential building blocks is already an important result for the SeleCHEM project.

2) New method to functionalize biomolecules, in particular proteins: in a team work with biologists, we were able to develop reagents able to selectively modify a single amino acid residue in proteins. Our "hypervalent iodine reagents" displayed unique reactivity and selectivity, and allow for example to introduce fluorescent molecules into proteins to study the biology of the cell. We can also use these reagents to identify the target of bioactive compounds, such as natural products and drugs, a process essential to develop new medication. Another application we developed in collaboration is the selective modification of antibodies, which opens the way for drug-antibody conjugates, with the potential for cures with less side effects. Finally, we were able to use our reagents to stabilize bioactive peptide, demonstrating increased binding affinity towards important targets for cancer therapy.

Our research is now continuing for a more selective chemistry (SeleCHEM) for both the modification of small synthetic compounds and large biomolecules.
Since January 2019, we have make significant progress in selective reactions going beyond the current state of the art in synthetic chemistry. This allowed us to develop new transformations in chemical biology. We are convinced that this is only a starting point, and the proof-of-principle selective processes developed since 2019 can now be expended to many more transformations, giving access to essential building blocks for drug synthesis and new tools to understand biology and develop lead compounds for drug discovery.
project abstract