title: Solid-phase synthesis of polymyxin B1 and analogues via a safety-catch approach.
abstract: 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.
authors.affiliation: Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, PO Box 9402, 2300 RA Leiden, The Netherlands.
authors.forename: P C
authors.initials: PC
authors.lastname: de Visser
authors.forename: N M A J
authors.initials: NM
authors.lastname: Kriek
authors.forename: P A V
authors.initials: PA
authors.lastname: van Hooft
authors.forename: A
authors.initials: A
authors.lastname: Van Schepdael
authors.forename: D V
authors.initials: DV
authors.lastname: Filippov
authors.forename: G A
authors.initials: GA
authors.lastname: van der Marel
authors.forename: H S
authors.initials: HS
authors.lastname: Overkleeft
authors.forename: J H
authors.initials: JH
authors.lastname: van Boom
authors.forename: D
authors.initials: D
authors.lastname: Noort
mesh_terms: D001407:Bacillus / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011113:Polymyxins / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D011113:Polymyxins; C121746:polymyxin B(1)