title: Sequence-defined bioactive macrocycles via an acid-catalysed cascade reaction.
abstract: Synthetic macrocycles derived from sequence-defined oligomers are a unique structural class whose ring size, sequence and structure can be tuned via precise organization of the primary sequence. Similar to peptides and other peptidomimetics, these well-defined synthetic macromolecules become pharmacologically relevant when bioactive side chains are incorporated into their primary sequence. In this article, we report the synthesis of oligothioetheramide (oligoTEA) macrocycles via a one-pot acid-catalysed cascade reaction. The versatility of the cyclization chemistry and modularity of the assembly process was demonstrated via the synthesis of >20 diverse oligoTEA macrocycles. Structural characterization via NMR spectroscopy revealed the presence of conformational isomers, which enabled the determination of local chain dynamics within the macromolecular structure. Finally, we demonstrate the biological activity of oligoTEA macrocycles designed to mimic facially amphiphilic antimicrobial peptides. The preliminary results indicate that macrocyclic oligoTEAs with just two-to-three cationic charge centres can elicit potent antibacterial activity against Gram-positive and Gram-negative bacteria.
authors.affiliation: School of Chemical and Biomolecular Engineering, Cornell University, 120 Olin Hall, Ithaca, New York 14850, USA.
authors.forename: Mintu
authors.initials: M
authors.lastname: Porel
authors.affiliation: School of Chemical and Biomolecular Engineering, Cornell University, 120 Olin Hall, Ithaca, New York 14850, USA.
authors.forename: Dana N
authors.initials: DN
authors.lastname: Thornlow
authors.affiliation: School of Chemical and Biomolecular Engineering, Cornell University, 120 Olin Hall, Ithaca, New York 14850, USA.
authors.forename: Ngoc N
authors.initials: NN
authors.lastname: Phan
authors.affiliation: School of Chemical and Biomolecular Engineering, Cornell University, 120 Olin Hall, Ithaca, New York 14850, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Alabi
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry; D002384:Catalysis; D002412:Cations; D003500:Cyclization; D047028:Macrocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry; D057786:Peptidomimetics; D011487:Protein Conformation
chemical_list: D000900:Anti-Bacterial Agents; D002412:Cations; D047028:Macrocyclic Compounds; D010455:Peptides; D057786:Peptidomimetics