P-03 - Molecular Life Sciences

Studies towards the total synthesis of retro-feglymycin

M.-A, J. Siegert, M. Tietzmann and R. D. Süßmuth

Institut für Chemie, Technische Universität Berlin, Straße des 17. Juni 124, 10623, Berlin, GER

The linear tridecapeptide feglymycin was isolated from Streptomyces sp. DSM 11171 in 1999.1 2 Feglymycin inhibits the formation of HIV syncytia and displays a strong antibacterial effect against Gram-positive bacteria. 3 It consists of a mainly alternating amino acid sequence and contains a high percentage of nonproteinogenic amino acids such as 4-hydroxyphenylglycine (Hpg) and 3,5-dihydroxyphenylglycine (Dpg).4 5 Due to its pharmacological activity, feglymycin is an interesting lead structure for the development of new biological active compounds.

The native feglymycin, which total synthesis was contributed by our group,6 has three analogue sequences: the inverso-peptide which has the same sequence but a mirror conformation, the retro-peptide which has the same sequence and conformation but in a reverse order and the retro-inverso-peptide consisting of the mirror conformation in the reversed sequence.

Inverso- retro- and retro-inverso-peptide of a compound are chemically completely different to the native peptide. Since amino acid sequence, chirality and direction of the peptide bond, can have an influence on the antibacterial activity, it is of great interest to synthesis the corresponding analogs, like it was already done with inverso-feglymycin. 7 Moreover, the synthesis of retro- and retro-inverso-feglymycin should provide information, how the variation of the peptide backbone and the phenolic side chains, which are potential hydrogen bond donors, have an influence on the antibacterial activity. A further interesting aspect is the influence of the altered N-and C-terminal charge distribution.

Aim of this work is the total synthesis of the tridecapeptide retro-feglymycin, followed by the evaluation of the potential of feglymycin as a lead structure for drugs.

  1. L. Vortesy, W. Aretz, M. Knauf, A. Markus, M. Vogel, J. Wink, J. Antibiot. 1999, 52, 374 – 382.

  2. L. Vortesy, M. Knauf, J. Wink, D. Isert, W. Stahl, G. Riess, J. Aszodi, D. Le Beller (Hoechst AG), EP-B1 0848064, 1998.

  3. S. Rausch, A. Hänchen, A. Denisiuk, M. Löhken, T. Schneider, R.D. Süssmuth, ChemBioChem 2011, 12, 1171–1173.

  4. L. Vértesy, W. Aretz, M. Knauf, A. Markus, M. Vogel, J. Wink, J. Antibiot. 1999, 52, 374–382.

  5. R. S. Al Toma, C. Brieke, M. J. Cryle, R. D. Süssmuth, Nat. Prod. Rep. 2015, 32, 1207–1235.

  6. F. Dettner, A. Hänchen, D. Schols, L. Toti, A. Nußer, R. D. Süssmuth, Angew. Chem. Int. Ed., 2009, 48, 1856-1861.

  7. Dissertation Dr. A. Hänchen, Technische Universität Berlin 2011.