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Synthesis and Conformational Analysis of Efrapeptins
Author(s) -
Weigelt Sven,
Huber Thomas,
Hofmann Frank,
Jost Micha,
Ritzefeld Markus,
Luy Burkhard,
Freudenberger Christoph,
Majer Zsuzsanna,
Vass Elemér,
Greie JörgChristian,
Panella Lavinia,
Kaptein Bernard,
Broxterman Quirinus B.,
Kessler Horst,
Altendorf Karlheinz,
Hollósi Miklós,
Sewald Norbert
Publication year - 2012
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201102134
Subject(s) - chemistry , stereochemistry , nuclear magnetic resonance spectroscopy , peptide , amino acid , alanine , side chain , helix (gastropod) , two dimensional nuclear magnetic resonance spectroscopy , cationic polymerization , spectroscopy , crystallography , organic chemistry , biochemistry , ecology , physics , quantum mechanics , snail , biology , polymer
The efrapeptin family of peptide antibiotics produced by the fungus Tolypocladium niveum , and the neo‐efrapeptins from the fungus Geotrichum candidum are inhibitors of F 1 ‐ATPase with promising antitumor, antimalaria, and insecticidal activity. They are rich in C α ‐dialkyl amino acids (Aib, Iva, Acc) and contain one β‐alanine and several pipecolic acid residues. The C‐terminus bears an unusual heterocyclic cationic cap. The efrapeptins C–G and three analogues of efrapeptin C were synthesized using α‐azido carboxylic acids as masked amino acid derivatives. All compounds display inhibitory activity toward F 1 ‐ATPase. The conformation in solution of the peptides was investigated with electronic CD spectroscopy, FT‐IR spectroscopy, and VCD spectroscopy. All efrapeptins and most efrapeptin analogues were shown to adopt helical conformations in solution. In the case of efrapeptin C, VCD spectra proved that a 3 10 ‐helix prevails. In addition, efrapeptin C was conformationally studied in detail with NMR and molecular modeling. Besides NOE distance restraints, residual dipolar couplings (RDC) observed upon partial alignment with stretched PDMS gels were used for the conformational analysis and confirmed the 3 10 ‐helical conformation.