76 アンジオテンシンI変換酵素の新規阻害物貭K-26およびK-4の構造

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Two new specific inhibitors of angiotensin I converting enzyme, K-26 and K-4, were isolated from the culture broth of Actinomycetes. IC_<50> of K-26 and K-4 were 6 and 80ng/ml, respectively. In anesthetized rats, inhibitory activity of the pressor response to angiotensin I by K-26 injected intravenously was comparable to that by captopril. Acid hydrolysis of K-26 gave each one mole of (-)-1-amino-2-(4-hydroxyphenyl)ethylphosphonic acid ((-)-Tyr-P), L-Ile, L-Tyr and acetic acid. Its structure was deduced to be N-Ac-L-Ile-L-Tyr-(-)-Tyr-P from detailed ^<13>C-NMR experiments. On the other hand, the structure of K-4, N-Me-Val-L-Phe-(-)-Tyr-P was also deduced on the basis of hydrolysis, ^<13>C-NMR and MS spectroscopies of its TMS-derivative. In order to determine not only the structures of K-26 and K-4 but also the absolute configurations of (-)-Tyr-P and N-Me-Val, these two compounds were synthesized by several steps from racemic diethyl 1-amino-2-(4-benzyloxyphenyl)ethylphosphonate. The synthetic materials were chromatographically and spectroscopically indistinguishable from the natural products and exhibited the same level of ACE inhibition. The absolute configuration of (-)-Tyr-P was unequivocally determined to be (R) by X-ray analysis of diethyl ester of K-26 (8a). Consequently, the structures of K-26 and K-4 were confirmed as shown in Fig. 5.
天然有機化合物討論会の論文
1985-09-07