Synthesis of New-to-Nature Atropopeptides by SNAr Macrocyclization for Medicinal Chemistry

Objective

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a large and diverse class of natural products that are fundamental to current drug discovery and development. Most of these peptides contain at least one macrocycle and many bear a stereogenic axis on a tryptophan motif, giving rise to atropisomeric macrocyclic peptides. Atropisomers are intrinsically non-planar, bearing shapes that often minimize the entropic penalty upon their binding to biological receptors, often enhancing potency, selectivity or metabolic stability. Nonetheless, drug discovery efforts have been hampered by lack of synthesis methods toward these peptidic atropisomeric molecules. For instance, there is currently no method for peptide macrocyclization toward C–N atropopeptides directly carried out on the indole of tryptophan. Accordingly, in RIPP-SNAr I will develop the first examples of such peptide macrocyclizations, taking advantage of catalytic nucleophilic aromatic substitution (SNAr). The main advantages are: 1) easy access to starting materials; 2) high modularity allowing for incorporation of structural diversity and 3) several possibilities for controlling atroposelective and atropodiastereodivergency. RIPP-SNAr will therefore provide more sustainable organic synthesis and, because new molecules will be tested biologically, may lead to new anticancer or antibacterial entities. My previous experience in synthesis and medicinal chemistry, acquired as PhD student in the United States, will be relevant to the realization of the project; the hallmark of RIPP-SNAr is the symbiosis between my previous experience in synthesis and medicinal chemistry with the experience in stereoselective catalysis from the host group, inserted at IOCB Prague with its long tradition on such interdisciplinary research. This fellowship will ensure that I become a strong candidate for a leadership position in the pharmaceutical industrial sector.