On-resin cyclization and antimicrobial activity of Laterocidin and its analogues

Total synthesis of cyclodecapeptide antibiotics from Bacillus laterosporus, laterocidin and its analogues, was accomplished for the first time by solid-phase peptide synthesis followed by traceless on-resin cyclization of the linear precursors with protection of α-carboxyl group on the Asp residue by Dmab as a temporary blocking group for on-resin head-to-tail cyclization, in which the carboxyl group of side chain of Asp was linked to Rink resin. Single alanine substitution or Asn substitution (Asp10→Asn10) demonstrated improvements in antibacterial activity. Of note, d-Phe2 and Pro4 play an important role in on-resin head-to-tail cyclization and exerting antibacterial activity of Laterocidin.

Graphical abstractTotal synthesis of naturally occurring Laterocidin and its alanine-scanning analogues with the side chain carboxyl group of Aspartate linked to Rink resin, and the α-carboxyl group of Aspartate protected by Dmab group as a temporary blocking group for on-resin head-to-tail cyclization of the linear precursor is reported.Download full-size image