Synthesis and biological evaluation of potential threonine synthase inhibitors: Rhizocticin A and Plumbemycin A

Bioorg Med Chem. 2013 Sep 1;21(17):4958-67. doi: 10.1016/j.bmc.2013.06.064. Epub 2013 Jul 8.

Abstract

Rhizocticins and Plumbemycins are natural phosphonate antibiotics produced by the bacterial strains Bacillus subtilis ATCC 6633 and Streptomyces plumbeus, respectively. Up to now, these potential threonine synthase inhibitors have only been synthesized under enzymatic catalysis. Here we report the chemical stereoselective synthesis of the non-proteinogenic (S,Z)-2-amino-5-phosphonopent-3-enoic acid [(S,Z)-APPA] and its use for the synthesis of Rhizocticin A and Plumbemycin A. In this work, (S,Z)-APPA was synthesized via the Still-Gennari olefination starting from Garner's aldehyde. The Michaelis-Arbuzov reaction was used to form the phosphorus-carbon bond. Oligopeptides were prepared using liquid phase peptide synthesis (LPPS) and were tested against selected bacteria and fungi.

Keywords: (S,Z)-APPA; Phosphonate antibiotic; Plumbemycin; Rhizocticin; Threonine synthase inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2-Amino-5-phosphonovalerate / analogs & derivatives
  • 2-Amino-5-phosphonovalerate / chemical synthesis
  • 2-Amino-5-phosphonovalerate / chemistry
  • Anti-Infective Agents / chemical synthesis*
  • Anti-Infective Agents / chemistry
  • Anti-Infective Agents / pharmacology
  • Bacillus subtilis / metabolism
  • Carbon-Oxygen Lyases / antagonists & inhibitors*
  • Carbon-Oxygen Lyases / metabolism
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Fungi / drug effects
  • Fungi / enzymology
  • Gram-Negative Bacteria / drug effects
  • Gram-Negative Bacteria / enzymology
  • Gram-Positive Bacteria / drug effects
  • Gram-Positive Bacteria / enzymology
  • Oligopeptides / chemical synthesis*
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology
  • Organophosphorus Compounds / chemical synthesis*
  • Organophosphorus Compounds / chemistry
  • Organophosphorus Compounds / pharmacology
  • Stereoisomerism
  • Streptomyces / metabolism

Substances

  • Anti-Infective Agents
  • Enzyme Inhibitors
  • Oligopeptides
  • Organophosphorus Compounds
  • rhizocticin A
  • 2-amino-5-phosphono-3-pentenoic acid
  • plumbemycin A
  • 2-Amino-5-phosphonovalerate
  • Carbon-Oxygen Lyases
  • threonine synthase