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Synthesis of molecular probes for cancer research based on priviliged natural products through a novel enantioselective oxidative arylation technology

Final Report Summary - PYRROLOINDOLE (Synthesis of molecular probes for cancer research based on priviliged natural products through a novel enantioselective oxidative arylation technology.)

The generous funding received from the Research Executive Agency through the Marie Curie Actions has made possible to start a research program on the field of protein labelling based on a fundamental breakthrough in hypervalent iodine chemistry.
Originally, the “Pyrroloindole” program was aimed at labelling important classes of natural products involved in the regulation of gene expression. The labelling event was planned to take advantage of novel arylation technology pioneered in the Gaunt group using diaryliodonium salts. Various reports in top international journals pursued this same concept just before the incorporation of the Fellow into the Host group in 2012 and throughout 2013.7 The great versatility of diaryliodonium salts permitted to refocus on the labelling of proteins, a more important and general class of biomolecules.
This problem was approached from the idea of expressing unnatural diaryliodonium aminoacids using orthogonal translational machinery. This new type of protein expression has been intensively developed in the last few years at the MRC Laboratory of Molecular Biology at Cambridge. The technology allows obtaining any desired protein incorporating unnatural functionalization at any desired position. As such, it was targeted to obtain diaryliodonium-tagged proteins using these tools. The iodonium functionality has demonstrated its versatility to perform cross-coupling reactions using carbon and heteroatomic nucleophiles of, virtually, any sort. As such, our efforts were fuelled by the promise of achieving protein labelling in a divergent way and discover new chemistry on doing so.
At the planning stage, we realized that despite the extensive studies on the reactivity of diaryliodonium species, there was no chemical knowledge on how to elaborate them conserving the iodonium functionality intact.
We did identify the first set of basic reactions that allow the cross-coupling of iodonium salts into common functional groups found in biomolecules (conserving the iodonium salt intact). Interestingly, we found conditions for efficient couplings involving nucleophiles and copper-catalysis, both known to react with diaryliodonium salts. The coupling reactions were based on imine and hydrazone condensation, ylide olefination, acylation and alkyne-azide cycloaddition (click chemistry). From a basic point of view, these findings re-adjust the existing dogma on hypervalent iodonium chemistry. It was demonstrated that these species were amenable to be transported through synthetic sequences, a concept that was unknown before.
Then, we took advantage of this knowledge to devise and optimize a synthetic route to the first diaryliodonium-aminoacid conjugates. These molecules are ready to initiate research at the MRC aimed at their orthogonal expression in living cells. Alternatively, the knowledge gained on the alkyne-azide cycloaddition reaction on iodonium salts enables access to the same protein-iodonium conjugates using available technology (through orthogonal translation of alkyne-containing proteins). Both approaches are being pursued at the moment in Cambridge.