Solid-phase synthesis of a cyclic decapeptide, analog of the antibiotic polymyxin M

Pelargonoyl-cyclo[Dab-Thr-Dab-Dab(Pel)-Dab-D-Leu-Thr-Dab-Dab-Thr]. 5 HCl (5), analog of the polymyxin M, has been synthesized by the solid phase method. The intermediate linear Boc-protected decapeptide-resin (1) was assembled on the solid support by the stepwise addition of Boc-amino acids in the presence of DCC. For side-chain protection of diaminobutyric acid, Z-group was used. The peptide was cleaved from the resin in the form of methyl ester by triethylamine-catalyzed transesterification with methanol. Alkaline hydrolysis of the peptide ester with aqueous KOH (1 mol/l) afforded the Bocpenta-benzyloxycarbonyl-decapeptide acid (2) in 60% yield (based on Thr/resin). After removal of the Boc-group, the linear peptide 3 was cyclized with DCC in high dilution in DMF (10(-3) mol/l) to give 4 in 51% yield. Hydrogenolysis of 4 in 80% formic acid afforded the pelargonyl cyclic decapeptide 5 in 74% yield. The synthetic peptide 5 retained the same activity of the natural polymyxin M against Bacillus subtilis and Staphylococcus aureus, whereas it showed only 3% of the activity of Escherichia coli.