P-63 環状イソジチロシン構造を有する海洋由来天然物ユーリパミド類縁体の合成と抗メチシリン耐性黄色ブドウ球菌活性(ポスター発表の部)

概要

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The 17-membered isodityrosine-containing cyclic-tripeptide eurypamide analogues of marine origin were found to be selective potentiation agents of imipenem against methicillin-resistant Staphylococcus aureus (MRSA). The eurypamide analogues were synthesized using thallium oxidation as key coupling reaction to construct the biaryl ether linkage in good yield. Thus, suitably substituted cyclization intermediate tripeptide Tyr-Thr-Tyr was connected sequentially through peptide bonds by general strategy. The crucial cyclization with thallium trinitrate (TTN) provided halogenated eurypamide B analogues in 90% yield as best (Scheme 1). Their antibacterial activity and cytotoxicity were examined. As reported, eurypamide B showed no antibacterial activity, while synthesized analogues showed anti-MRSA activity when used combined with imipenem, even under low ineffective concentration of imipenem against MRSA. From structure activity relationship study, the C-terminal carboxylic acid was found to be important to show the potent activity. These analogues are expected to be useful as a lead for new anti-MRSA agents with low toxicity. Solid-phase synthesis was also established to obtain more variety of analogues easily. Moreover, fluorescent label was introduced to the N-terminal moiety to determine the biological target.
天然有機化合物討論会の論文
2005-09-15