title: Rapid total synthesis of cyclic lipodepsipeptides as a premise to investigate their self-assembly and biological activity.
abstract: A rapid and efficient total synthesis is reported for the cyclic lipodepsipeptide pseudodesmin A. This member of the Pseudomonas viscosin group is active against Gram-positive bacteria and features self-assembling properties. A conserved serine residue within the lactone macrocycle is exploited for initial immobilization on 2-chlorotrityl chloride resin through ether formation with the side-chain alcohol. Subsequent elongation proceeds through Fmoc solid-phase peptide synthesis, including automated incorporation of the enantioselectively synthesized (R)-3-hydroxydecanoic acid lipid tail. Following esterification to generate the incipient lactone bond, the macrocycle is formed by on-resin head-to-tail macrolactamization and cleaved from the resin to give the desired compound in good purity. The short and efficient synthesis route allows rapid generation of analogues by facile variation of both the peptide and lipid moieties with good control of epimerization while maximizing automation. Synthesis of the pseudodesmin A enantiomer yields identical self-assembly and biological activity to that observed for the natural compound, showing that activity is not mediated by chiral interactions. A D-Asn8 analogue developed en route retains self-assembly, but loses activity. The synthesis strategy should be generally applicable for the rapid generation of analogues from various cyclic lipodepsipeptide groups, allowing an investigation of their self-assembling properties and structure-activity relationships.
authors.affiliation: Department of Organic Chemistry, Organic and Biomimetic Chemistry Research Group, Ghent University, Krijgslaan 281 S4, 9000 Ghent (Belgium); Department of Organic Chemistry, NMR and Structure Analysis Unit, Ghent University, Krijgslaan 281 S4, 9000 Ghent (Belgium).
authors.forename: Matthias
authors.initials: M
authors.lastname: De Vleeschouwer
authors.forename: Davy
authors.initials: D
authors.lastname: Sinnaeve
authors.forename: Jos
authors.initials: J
authors.lastname: Van den Begin
authors.forename: Tom
authors.initials: T
authors.lastname: Coenye
authors.forename: José C
authors.initials: JC
authors.lastname: Martins
authors.forename: Annemieke
authors.initials: A
authors.lastname: Madder
mesh_terms: D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry*; D010456:Peptides, Cyclic / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D010455:Peptides; D010456:Peptides, Cyclic; C062796:viscosin
keywords: peptides; self-assembly; solid-phase synthesis; structure-activity; total synthesis