PYRROLOINDOLE

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

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 Obiettivo del progetto (Objective)

'Enantioselective catalysis continues to be a necesarily expanding part of Organic Chemistry and Synthesis to be able to provide the enantiopure compounds that Society demands in a straightforward and sustainable way. This research proposal is aimed at doing so through the development of new enantioselective oxidative arylation reactions a completely unprecedented research field. Moreover, the molecular structures and synthetic targets have been selected in close collaboration with the group of Dr. Murrell at CRUK Cambridge. This collaboration is aimed at understanding the processes of cancer generation and growth at the molecular level through development of small molecule histone methylation and acetylation modulators. To study such processes a priviliged and synthetically challenging familiy of natural products is targeted: the pyrroloindole alkaloids. Development of molecular probes inspired by these products and demonstration of the total synthesis of some members will be accomplished through the development of appropiate chemical tools. The synthesis of these compounds will enable multidisciplinar research to study the particularities of oncogenesis.'

Introduzione (Teaser)

Diaryliodonium salts belong to the important class of hypervalent iodine compounds. The great versatility of diaryliodonium salts permits their use for the labelling of proteins and creation of important artificial biomolecules.

Descrizione progetto (Article)

The EU-funded Marie Curie Actions project PYRROLOINDOLE initiated a research program on protein labelling based on a fundamental breakthrough in hypervalent iodine chemistry. Originally, the study aimed at labelling important classes of natural products involved in the regulation of gene expression. However, focus was redirected towards the idea of creating diaryliodonium aminoacids using orthogonal translational machinery.

The technology permits the development of any protein incorporating novel functional groups at the position of choice. The iodonium functionality has demonstrated its versatility to perform cross-coupling reactions using carbon and heteroatomic nucleophiles of virtually any sort. This technology was applied to obtain a variety of diaryliodonium-tagged proteins.

Researchers identified the first set of basic reactions that allow the cross-coupling of iodonium salts into common functional groups found in biomolecules. They established 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, acylation and alkyne-azide cycloaddition. 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.

These discoveries were used to devise and optimise a synthetic route to the first diaryliodonium-aminoacid conjugates. Alternatively, access to the same protein-iodonium conjugates was carried out using available technology of orthogonal translation of alkyne-containing proteins. Currently, these molecules are under investigation for their orthogonal expression in living cells.

PYRROLOINDOLE project demonstrated that the total synthesis of new molecular probes could be accomplished through the development of appropriate chemical tools. These compounds might enable novel research developments in different biomedical applications.