Solid-phase synthesis of polymyxin B1 and analogues via a safety-catch approach
article
As part of a program towards the development of novel antibiotics, a convenient method for solid-phase synthesis of the cyclic cationic peptide polymyxin B1 and analogues thereof is described. The methodology, based on cleavage-by-cyclization using Kenner's safety-catch linker, yields crude products with purities ranging from 37-67%. Antibacterial assays revealed that analogues 23-26, in which the (S)-6-methyloctanoic acid moiety is replaced with shorter acyl chains, exhibit distinct antimicrobial activity. The results suggest that the length of the acyl chain is rather critical for antimicrobial activity. On the other hand, substitution of the hydrophobic ring-segment D-Phe-6/Leu-7 in polymyxin B1 with dipeptide mimics (i.e. analogues 27-33) resulted in almost complete loss of antimicrobial activity.
Topics
AntibioticsCationic peptidePolymyxinSafety-catch linkerSolid-phase synthesis6 methyloctanoic acidDextro phenylalanineLeucine 61-90-5, 7005-03-0Octanoic acid derivativePolymyxin derivativeUnclassified drugAcylationAntibacterial activityCyclizationDrug potencyDrug purificationDrug structureDrug synthesisHigh performance liquid chromatographyHydrophobicitySolid stateBacillusChromatography, High Pressure LiquidMicrobial Sensitivity TestsMolecular StructurePolymyxinsStructure-Activity RelationshipPolymyxin B(1), 4135-11-9Polymyxins
TNO Identifier
237115
ISSN
1397002X
Source
Journal of Peptide Research, 61(6), pp. 298-306.
Pages
298-306
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