22 バンコマイシン類の合成と分子認識(口頭発表の部)

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The glycopeptide antibiotic vancomycin is well known as a therapeutic drug in the treatment of methicillin resistant Staphylococcus aureus (MRSA) infection. The bactericidal activity is explained by the high affinity of this antibiotic to the terminal D-alanyl-D-alanine residue of peptidoglycan precursors in bacterial cell wall biosynthesis. Synthesis of secoaglucovancomycins (3 and 4), vancomycin analogs, has been accomplished. The biphenyl ether moiety was successfully constructed by means of thallium (III) oxidation of the corresponding halogenated tetrapeptides. Further peptide chain elongation gave the corresponding heptapeptide, and final ring closure was undertaken under the same oxidation conditions. The following deprotection and dehalogenation gave secoaglucovancomycin-1 (3) and 2 (4). The conformational analysis of these compounds is also discussed by means of ^1HNMR studies and molecular dynamics calculation (CHARMm). Secoaglucovancomycin possessed more flexible conformers than agulucovancomycin, due to the lack of the biphenyl linkage. The binding structure of these molecules with the models of bacterial cell wall is also discussed. The complexes were experimentally obtained by the co-solution of 3 or 4 with N-acetyl-D-alanyl-D-alanine. The properties estimated by ^1HNMR techniques, were different from that of aglucovancomycin. Consequently, the binding structures were also examined by molecular dynamics calculations. The synthetic aglucovancomycins were interacted by five hydrogen bondings to the model peptide, which is different from the natural case. This binding mode strongly suggested a possibility that such compounds will be effective against vancomycin resistant strains, which have terminal D-alanyl-D-lactic acid as cell wall precursor.
天然有機化合物討論会の論文
1996-09-02

22 バンコマイシン類の合成と分子認識(口頭発表の部)

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