Solid‐phase total synthesis of polymyxin B1

Abstract

The total solid-phase synthesis of polymyxin B1 (PMB1) has been achieved in 20% yield using the orthogonal protecting group N-1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl-(Dde). This report demonstrates that a complex peptide macrocycle can be synthesized in high yields using solid-phase synthesis. According to MS and HPLC, the synthetic peptide was identical to the naturally occurring antibiotic.

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.…”

“…5,6) These interactions lead to disordering of Gram-negative bacterial cell membranes, resulting in cell death. 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.…”

Structure−Activity Relationships of Polymyxin Antibiotics

“…Such protection provides a mechanism to yield a partially protected linear precursor amenable to cyclization (Figure 7). This has been somewhat challenging, as protected l -Dab residues are not so readily accessible, but in recent years examples such as Fmoc- l -Dab tert -Bbutyloxycarbonyl (Boc),69 Fmoc- l -Dab 1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethyl (Dde),70 Fmoc- l -Dab 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl (ivDde),71 Fmoc- l -Dab 4-methyltrityl (Mtt),72 and Fmoc- l -Dab 2-chlorobenzyloxycarbonyl (2-ClZ)73 have been described.…”

Identification of a Polymyxin Synthetase Gene Cluster of Paenibacillus polymyxa and Heterologous Expression of the Gene in Bacillus subtilis

“…Recently, total or semisynthesis or modifications of polymyxins was performed chemically or enzymatically, and the resulting products were effectively used for structure-function study (6,20,36,45,50,52). There is a limitation to obtaining diverse derivatives by using chemical or enzymatic approaches, however, and this limitation is related to the structural complexity of polymyxin.…”