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Rapid total synthesis of cyclic lipodepsipeptides as a premise to investigate their self-assembly and biological activity

Matthias De Vleeschouwer (UGent) , Davy Sinnaeve (UGent) , Jos Van den Begin (UGent) , Tom Coenye (UGent) , José Martins (UGent) and Annemieke Madder (UGent)
(2014) CHEMISTRY-A EUROPEAN JOURNAL. 20(25). p.7766-7775
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Organization
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.
Keywords
self-assembly, solid-phase synthesis, peptides, total synthesis, structure-activity, GLYCOPEPTIDE THIOESTERS, PEPTIDE, LIPOPEPTIDES, DEPSIPEPTIDE, ANTIBACTERIAL, DIVERSITY, DIFFUSION, SOLID-PHASE SYNTHESIS, BETA-KETO-ESTERS, PSEUDOMONAS-FLUORESCENS

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Citation

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MLA
De Vleeschouwer, Matthias, et al. “Rapid Total Synthesis of Cyclic Lipodepsipeptides as a Premise to Investigate Their Self-Assembly and Biological Activity.” CHEMISTRY-A EUROPEAN JOURNAL, vol. 20, no. 25, 2014, pp. 7766–75, doi:10.1002/chem.201402066.
APA
De Vleeschouwer, M., Sinnaeve, D., Van den Begin, J., Coenye, T., Martins, J., & Madder, A. (2014). Rapid total synthesis of cyclic lipodepsipeptides as a premise to investigate their self-assembly and biological activity. CHEMISTRY-A EUROPEAN JOURNAL, 20(25), 7766–7775. https://doi.org/10.1002/chem.201402066
Chicago author-date
De Vleeschouwer, Matthias, Davy Sinnaeve, Jos Van den Begin, Tom Coenye, José Martins, and Annemieke Madder. 2014. “Rapid Total Synthesis of Cyclic Lipodepsipeptides as a Premise to Investigate Their Self-Assembly and Biological Activity.” CHEMISTRY-A EUROPEAN JOURNAL 20 (25): 7766–75. https://doi.org/10.1002/chem.201402066.
Chicago author-date (all authors)
De Vleeschouwer, Matthias, Davy Sinnaeve, Jos Van den Begin, Tom Coenye, José Martins, and Annemieke Madder. 2014. “Rapid Total Synthesis of Cyclic Lipodepsipeptides as a Premise to Investigate Their Self-Assembly and Biological Activity.” CHEMISTRY-A EUROPEAN JOURNAL 20 (25): 7766–7775. doi:10.1002/chem.201402066.
Vancouver
1.
De Vleeschouwer M, Sinnaeve D, Van den Begin J, Coenye T, Martins J, Madder A. Rapid total synthesis of cyclic lipodepsipeptides as a premise to investigate their self-assembly and biological activity. CHEMISTRY-A EUROPEAN JOURNAL. 2014;20(25):7766–75.
IEEE
[1]
M. De Vleeschouwer, D. Sinnaeve, J. Van den Begin, T. Coenye, J. Martins, and A. Madder, “Rapid total synthesis of cyclic lipodepsipeptides as a premise to investigate their self-assembly and biological activity,” CHEMISTRY-A EUROPEAN JOURNAL, vol. 20, no. 25, pp. 7766–7775, 2014.
@article{5684091,
  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.}},
  author       = {{De Vleeschouwer, Matthias and Sinnaeve, Davy and Van den Begin, Jos and Coenye, Tom and Martins, José and Madder, Annemieke}},
  issn         = {{0947-6539}},
  journal      = {{CHEMISTRY-A EUROPEAN JOURNAL}},
  keywords     = {{self-assembly,solid-phase synthesis,peptides,total synthesis,structure-activity,GLYCOPEPTIDE THIOESTERS,PEPTIDE,LIPOPEPTIDES,DEPSIPEPTIDE,ANTIBACTERIAL,DIVERSITY,DIFFUSION,SOLID-PHASE SYNTHESIS,BETA-KETO-ESTERS,PSEUDOMONAS-FLUORESCENS}},
  language     = {{eng}},
  number       = {{25}},
  pages        = {{7766--7775}},
  title        = {{Rapid total synthesis of cyclic lipodepsipeptides as a premise to investigate their self-assembly and biological activity}},
  url          = {{http://doi.org/10.1002/chem.201402066}},
  volume       = {{20}},
  year         = {{2014}},
}
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