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.

Contribution of Each Amino Acid Residue in Polymyxin B3 to Antimicrobial and Lipopolysaccharide Binding Activity

“…The cyclization reaction proceeded quantitatively in a high concentration (ca. 0.01 mmol/ml) solution of 1 L -16 L to yield 1 C -16 C , which were treated with HF to yield polymyxin B analogs (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). The purity of the synthetic peptides was Ͼ97% as shown representatively in Fig.…”

“…7) Since the total solid phase synthesis of polymyxin B 1 was first reported by Sharma in 1999, 8) various polymyxin B analogs have been synthesized and evaluated for biological activity. [9][10][11][12][13][14][15][16][17] However, the structure-activity relationship of polymyxin B peptides is not understood in detail, due to the lack of extensive works employing highly pure peptides. We previously reported a study aimed at clarifying the contribution of the N-terminal fatty acyl groups of various polymyxin B family peptides to biological activity, as well as the development of N-terminal analogs without fatty acyl groups.…”

A Novel Chemical Biology Approach for Mapping of Polymyxin Lipopeptide Antibody Binding Epitopes

“…32–40 Not surprisingly, most discovery programs have concentrated on generating semi-synthetic N -terminal analogs in an effort to discover safer polymyxins. 36–38, 41 The SPR epitope mapping data reveal that the mAb strongly recognized the octanoyl fatty acyl chain of the native polymyxin scaffold, as removal of the fatty acyl chain (colistin nonapeptide) abolished the binding.…”

Development of new polymyxin derivatives for multi-drug resistant Gram-negative infections

“…The use of the Kenner 'safety-catch' approach in which release from the resin was effected by the cyclisation step was investigated by De Visser et al 48 Although promising, the low yield of the required sulfonamide-linked threonine may be the reason why this approach has not been developed further.…”