Semi-synthesis of polymyxin B (2-10) and colistin (2-10) analogs employing the Trichloroethoxycarbonyl (Troc) group for side chain protection of alpha,gamma-diaminobutyric acid residues

Chem Pharm Bull (Tokyo). 2007 Dec;55(12):1724-30. doi: 10.1248/cpb.55.1724.

Abstract

Improved strategies for the chemical conversion of natural polymyxin B and colistin to their N-terminal analogs are reported. First, the protection of the side chains of five L-alpha,gamma-diaminobutyric acid (Dab) residues in natural polymyxin B and colistin was achieved with trichloroethoxycarbonyl (Troc), then the resulting pentakis(N gamma-Troc)-polymyxin B and pentakis(N gamma)Troc)-colistin were treated with trifluoroacetic acid (TFA) : methanesulfonic acid (MSA) : dimethylformamide (DMF) : H2O (10 : 30 : 55 : 5) at 40 degrees C in order to remove N alpha-alkanoyl-Dab(Troc)-OH selectively. The new key compounds, tetrakis(N gamma-Troc)-polymyxin B (2-10) and tetrakis(N gamma-Troc)-colistin (2-10), were obtained in 19% and 15% yields, respectively, which is higher than previous reports using trifluoroacetyl (Tfa) for tetrakis(N gamma-Tfa)-polymyxin B (2-10) and tetrakis(N gamma-Tfa)-colistin (2-10), respectively. Acylation of tetrakis(N gamma-Troc)-polymyxin B (2-10) and tetrakis(N gamma-Troc)-colistin (2-10) with various hydrophobic acids bearing aliphatic or aromatic ring structures, followed by the deprotection of Troc by Zn in AcOH, produced polymyxin B (2-10) and colistin (2-10) analogs which were used for structure-activity relationship studies. It was found that cyclohexylbutanoyl-, 4-biphenylacetyl-, and 1-adamantaneacetyl-polymyxin B (2-10) showed potent antimicrobial activity equal to that of polymyxin B against three Gram-negative bacterial strains. The lipopolysacharide (LPS) binding activity of cyclohexylbutanoyl-, 4-biphenylacetyl-, and cyclododecanecarbonyl-polymyxin B (2-10) increased greatly in comparison with that of polymyxin B (2-10). The various N alpha-acylated polymyxin B (2-10) analogs showed slightly higher antimicrobial and LPS binding activities than the corresponding N alpha-acylated colistin (2-10) analogs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Acylation
  • Aminobutyrates / chemistry*
  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / pharmacology*
  • Bacteria / drug effects
  • Binding, Competitive / drug effects
  • Biopolymers / chemistry*
  • Chromatography, High Pressure Liquid
  • Colistin / analogs & derivatives*
  • Colistin / chemical synthesis*
  • Escherichia coli / metabolism
  • Hydrocarbons, Chlorinated / classification*
  • Indicators and Reagents
  • Lipopolysaccharides / chemistry
  • Lipopolysaccharides / metabolism
  • Microbial Sensitivity Tests
  • Polymyxin B / analogs & derivatives*
  • Polymyxin B / chemical synthesis*
  • Spectrometry, Mass, Fast Atom Bombardment

Substances

  • Aminobutyrates
  • Anti-Bacterial Agents
  • Biopolymers
  • Hydrocarbons, Chlorinated
  • Indicators and Reagents
  • Lipopolysaccharides
  • gamma-poly-alpha,gamma-diaminobutyric acid
  • Polymyxin B
  • Colistin