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.
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.
Faculty of Pharmaceutical Sciences, Hokuriku University, Kanagawa-machi, Kanazawa 920-1181, Japan.
Keiko
K
Okimura
Kazuhiro
K
Ohki
Yuki
Y
Sato
Kuniharu
K
Ohnishi
Naoki
N
Sakura
D000107:Acetylation; D000215:Acylation; D000613:Aminobutyrates / Q000737:chemistry*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D001704:Biopolymers / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D003091:Colistin / Q000031:analogs & derivatives* / Q000138:chemical synthesis*; D004926:Escherichia coli / Q000378:metabolism; D006843:Hydrocarbons, Chlorinated / Q000145:classification*; D007202:Indicators and Reagents; D008070:Lipopolysaccharides / Q000737:chemistry / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D011112:Polymyxin B / Q000031:analogs & derivatives* / Q000138:chemical synthesis*; D016339:Spectrometry, Mass, Fast Atom Bombardment
D000613:Aminobutyrates; D000900:Anti-Bacterial Agents; D001704:Biopolymers; D006843:Hydrocarbons, Chlorinated; D007202:Indicators and Reagents; D008070:Lipopolysaccharides; C057097:gamma-poly-alpha,gamma-diaminobutyric acid; D011112:Polymyxin B; D003091:Colistin