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

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-α,γ-diaminobutyric acid (Dab) residues in natural polymyxin B and colistin was achieved with trichloroethoxycarbonyl (Troc), then the resulting pentakis(Nγ-Troc)-polymyxin B and pentakis(Nγ-Troc)-colistin were treated with trifluoroacetic acid (TFA): methanesulfonic acid (MSA): dimethylformamide (DMF) :H2O (10:30:55:5) at 40 ° C in order to remove Nαalkanoyl- Dab(Troc)-OH selectively. The new key compounds, tetrakis(Nγ- Troc)-polymyxin B (2-10) and tetrakis(Nγ-Troc)-colistin (2-10), were obtained in 19% and 15% yields, respectively, which is higher than previous reports using trifluoroacetyl (Tfa) for tetrakis(Nγ- Tfa)-polymyxin B (2-10) and tetrakis(Nγ-Tfa)-colistin (2-10), respectively.2) Acylation of tetrakis(Nγ-Troc)- polymyxin B (2-10) and tetrakis(Nγ-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 α-acylated polymyxin B (2-10) analogs showed slightly higher antimicrobial and LPS binding activities than the corresponding N α-acylated colistin (2-10) analogs. © 2007 Pharmaceutical Society of Japan.