Solid-Phase Synthesis of Octapeptin Lipopeptides

Karl A Hansford; Zyta M Ziora; Matthew A Cooper; Mark A T Blaskovich

doi:10.1007/978-1-0716-0227-0_13

Solid-Phase Synthesis of Octapeptin Lipopeptides

Methods Mol Biol. 2020:2103:199-213. doi: 10.1007/978-1-0716-0227-0_13.

Authors

Karl A Hansford¹, Zyta M Ziora², Matthew A Cooper², Mark A T Blaskovich²

Affiliations

¹ Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia. k.hansford@uq.edu.au.
² Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia.

PMID: 31879927
DOI: 10.1007/978-1-0716-0227-0_13

Abstract

Octapeptins are naturally derived cyclic lipopeptide antibiotics with activity against a range of Gram-negative pathogens, including highly resistant strains. Octapeptin C4, an exemplar of the class, was synthesized using a combination of Fmoc solid-phase peptide synthesis (SPPS) and solution-phase cyclization. Utilizing H-L-Leu-2-chlorotrityl resin, peptide couplings were performed using HCTU and collidine in DMF. The linear sequence was terminated by N-acylation with 3-(R)-hydroxydecanoic acid. The residue Dab-2 was orthogonally protected with 1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)isovaleryl group (ivDde) to enable selective side-chain deprotection prior to resin cleavage. Resin cleavage was accomplished with hexafluoroisopropanol in DCM, followed by cyclization with diphenylphosphoryl azide (DPPA) and solid sodium bicarbonate in DMF.

Keywords: Antibiotics; Cyclopeptides; Lipopeptides; Octapeptin; Solid-phase peptide synthesis.

MeSH terms

Azides
Chemistry Techniques, Synthetic
Chromatography, High Pressure Liquid
Cyclization
Hydrolysis
Lipopeptides / chemical synthesis*
Lipopeptides / isolation & purification
Molecular Structure
Peptides, Cyclic / chemical synthesis
Peptides, Cyclic / pharmacology
Solid-Phase Synthesis Techniques / methods*

Substances

Azides
Lipopeptides
Peptides, Cyclic
octapeptin antibiotics
diphenylphosphorazidate