J Berna (@jbernicano.bsky.social)

Development of Aromatic Foldamer Building Blocks Bearing Multiple Biogenic Side Chains Aromatic oligoamides, with their intrinsic rigidity and well-defined conformations, are recognized for their potential in medical applications. Similar structures are present in several naturally occurring antibiotics and have been explored for their ability to bind to various proteins and B-DNA (canonical right-handed DNA helix). This study introduces a synthetic approach to produce quinoline amino acid monomers bearing diversified side chain combinations in positions 4, 5, and 6 of the quinoline ring, designed to enhance the side chain density on helical foldamers. By increasing the number of side chains on each monomer, we aim to mimic the dense side chain presentation of α-peptides, thus improving the potential for protein surface recognition. This synthetic strategy involves efficient functionalization through cross-coupling reactions, enabling the installation of diverse side chains at strategic positions on the quinoline ring. The process has been optimized for automated solid-phase synthesis, successfully producing a 20-unit oligoamide with good purity. This foldamer, featuring multiple cationic, anionic, polar, and hydrophobic side chains, demonstrates the potential for molecular recognition in drug discovery and therapeutic applications. The methodology described here represents a significant advancement in the construction of aromatic oligoamide foldamers, providing a robust platform for further exploration of biological systems. https://pubs.acs.org/doi/10.1021/acs.joc.4c02900