Combined Approach of Backbone Amide Linking and On-Resin N-Methylation for the Synthesis of Bioactive and Metabolically Stable Peptides

Abstract

Rhabdopeptides are a large class of nonribosomal peptides from the bacteria Xenorhabdus and Photorhabdus with low micromolar activity against different protozoa, which are the causative agents of several tropical diseases. The development of a facile and flexible synthesis combining backbone amide linking with on-resin peralkylation for the synthesis of permethylated rhabdopeptides is described. This strategy allows the fast generation of permethylated naturally occurring and artificial rhabdopeptides for a structure-activity study. Furthermore, in vitro experiments revealed their superior properties regarding their stability and passive membrane diffusion.

Rhabdopeptide/Xenortide-like Peptides from Xenorhabdus innexi with Terminal Amines Showing Potent Antiprotozoal Activity

“…against T. brucei rhodesiense and can be regarded as a screening hit . Moreover, with efficient synthesis strategies in hand, one also might now even further optimize RXPs, with respect to their terminal amines, which obviously can also be polar, as we show in this work.…”

CRAGE enables rapid activation of biosynthetic gene clusters in undomesticated bacteria

“…Reactive groups were deactivated with 17:2:1 DCM/MeOH/DIPEA. All possible pentapeptides (15 total) that had l-configurations instead of the expected d-configurations at the α-carbons were automatically synthesized with a SYRO peptide synthesizer using Fmoc-protected amino acids, as described previously 55,81,82 .…”

Methionine-Containing Rhabdopeptide/Xenortide-like Peptides from Heterologous Expression of the Biosynthetic Gene Cluster kj12ABC in Escherichia coli

“…The synthesis was performed manually using stepwise solid-phase peptide synthesis (SPPS) method. , For a schematic overview and detailed steps, see Scheme and the Supporting Information.…”

“…Based on these preliminary results, we suggested the structures of 1 – 7 as shown in Figure . In order to confirm the proposed structures, compounds 1 – 7 were synthesized by using a solid-phase peptide synthesis method developed for the synthesis of partly methylated rhabdo­peptide/​xenortide-like peptides (Scheme ) , and compared to natural 1 – 7 regarding retention time and MS 2 fragmentation pattern (Figure S3).…”