659745-86-5Relevant articles and documents
Chemical conversion of natural polymyxin B and colistin to their N-terminal derivatives
Okimura, Keiko,Ohki, Kazuhiro,Sato, Yuki,Ohnishi, Kuniharu,Uchida, Yoshiki,Sakura, Naoki
, p. 543 - 552 (2008/09/18)
The chemical conversions of natural polymyxin B and colistin, which are fatty-acylated cyclic decapeptides, to polymyxin (2-10) and colistin (2-10) derivatives were examined. The Nα-free and side chain N γ-protected nonapeptides, i.e., tetrakis(Nγ- trifluoroacetyl)-polymyxin B (2-10) and tetrakis(Nγ- trifluoroacetyl)-colistin (2-10), were prepared by trifluoroacetylation of polymyxin B and colistin, followed by chemical cleavage with 50% methanesulfonic acid to remove Nα-alkanoyl-Nγ- trifluoroacetyl-Dab-OH. The Nγ-protected nonapeptides were useful starting materials for the semi-synthesis of N-terminal derivatives by selective Nα-acylation at Thr2, followed by the removal of the Nγ-trifluoroacetyl protecting group with aqueous piperidine. Further, myristoyl-polymyxin B (2-10) and myristoyl-colistin (2-10) retained their antimicrobial activity with an MIC of 2-4 nmol mL-1 against Escherichia coli, Salmonella Typhimurium, and Pseudomonas aeruginosa. They also retained their high lipopolysaccahride (LPS) binding activity. Acetyl-polymyxin B (2-10) and acetyl-colistin (2-10) exhibited very low biological activities, except for a high bactericidal activity specifically against Pseudomonas aeruginosa with an MIC of 2 nmol mL-1. The distinct sensitivity of three Gram-negative bacteria tested toward acetyl-nonapeptides suggested that the N-terminal hydrophobic character of the fatty-acylated polymyxin peptides was necessary for the bactericidal activity against Escherichia coli and Salmonella Typhimurium, but not against Pseudomonas aeruginosa.
