| Semi-synthesis of polymyxin B (2-10) and colistin (2-10) analogs employing the Trichloroethoxycarbonyl (Troc) group for side chain protection of alpha,gamma-diaminobutyric acid residues. | |
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MedLine Citation:
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PMID: 18057747 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Improved strategies for the chemical conversion of natural polymyxin B and colistin to their N-terminal analogs are reported. First, the protection of the side chains of five L-alpha,gamma-diaminobutyric acid (Dab) residues in natural polymyxin B and colistin was achieved with trichloroethoxycarbonyl (Troc), then the resulting pentakis(N gamma-Troc)-polymyxin B and pentakis(N gamma)Troc)-colistin were treated with trifluoroacetic acid (TFA) : methanesulfonic acid (MSA) : dimethylformamide (DMF) : H2O (10 : 30 : 55 : 5) at 40 degrees C in order to remove N alpha-alkanoyl-Dab(Troc)-OH selectively. The new key compounds, tetrakis(N gamma-Troc)-polymyxin B (2-10) and tetrakis(N gamma-Troc)-colistin (2-10), were obtained in 19% and 15% yields, respectively, which is higher than previous reports using trifluoroacetyl (Tfa) for tetrakis(N gamma-Tfa)-polymyxin B (2-10) and tetrakis(N gamma-Tfa)-colistin (2-10), respectively. Acylation of tetrakis(N gamma-Troc)-polymyxin B (2-10) and tetrakis(N gamma-Troc)-colistin (2-10) with various hydrophobic acids bearing aliphatic or aromatic ring structures, followed by the deprotection of Troc by Zn in AcOH, produced polymyxin B (2-10) and colistin (2-10) analogs which were used for structure-activity relationship studies. It was found that cyclohexylbutanoyl-, 4-biphenylacetyl-, and 1-adamantaneacetyl-polymyxin B (2-10) showed potent antimicrobial activity equal to that of polymyxin B against three Gram-negative bacterial strains. The lipopolysacharide (LPS) binding activity of cyclohexylbutanoyl-, 4-biphenylacetyl-, and cyclododecanecarbonyl-polymyxin B (2-10) increased greatly in comparison with that of polymyxin B (2-10). The various N alpha-acylated polymyxin B (2-10) analogs showed slightly higher antimicrobial and LPS binding activities than the corresponding N alpha-acylated colistin (2-10) analogs. |
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Authors:
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Keiko Okimura; Kazuhiro Ohki; Yuki Sato; Kuniharu Ohnishi; Naoki Sakura |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Chemical & pharmaceutical bulletin Volume: 55 ISSN: 0009-2363 ISO Abbreviation: Chem. Pharm. Bull. Publication Date: 2007 Dec |
Date Detail:
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Created Date: 2007-12-06 Completed Date: 2008-01-28 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0377775 Medline TA: Chem Pharm Bull (Tokyo) Country: Japan |
Other Details:
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Languages: eng Pagination: 1724-30 Citation Subset: IM |
Affiliation:
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Faculty of Pharmaceutical Sciences, Hokuriku University, Kanagawa-machi, Kanazawa 920-1181, Japan. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Acetylation Acylation Aminobutyric Acids / chemistry* Anti-Bacterial Agents / chemical synthesis*, pharmacology* Bacteria / drug effects Binding, Competitive / drug effects Biopolymers / chemistry* Chromatography, High Pressure Liquid Colistin / analogs & derivatives*, chemical synthesis* Escherichia coli / metabolism Hydrocarbons, Chlorinated / classification* Indicators and Reagents Lipopolysaccharides / chemistry, metabolism Microbial Sensitivity Tests Polymyxin B / analogs & derivatives*, chemical synthesis* Spectrometry, Mass, Fast Atom Bombardment |
| Chemical | |
Reg. No./Substance:
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0/Aminobutyric Acids; 0/Anti-Bacterial Agents; 0/Biopolymers; 0/Hydrocarbons, Chlorinated; 0/Indicators and Reagents; 0/Lipopolysaccharides; 1066-17-7/Colistin; 117153-91-0/gamma-poly-alpha,gamma-diaminobutyric acid; 1404-26-8/Polymyxin B |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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