73(P49) Strestomyces sp. P371の生産する胃酸分泌抑制物質-胃粘膜保護作用を併せ持つ抗ガストリン作用物質-について(ポスター発表の部)

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In the course of a screening program to discover new anti-ulcer agents from Actinomycetes, we isolated a novel angucycline series compound P371A1 (1) and A2 (2) from Streptomyces sp. P371, together with other congeners P371B1 and P371B2. The molecular formula of P371A1 (1) was established to be C_<48>H_<66>N_2O_<20> based on the HRFAB-MS and ^<13>C NMR spectra. It was demonstrated through the analyses of the 1D- and 2D- NMR spectra and MS/MS spectra, together with some derivatizations that 1 is a novel angucycline series compound consisting of the angucycline unit (X_1-X_2) and the four sugar units (X_3, X_4, X_5 and X_6) as shown in Fig 2. P371A2 (2) was elucidated to be the C-4 acetoxy derivative of 1 through comparison of their ^1H- and ^<13>C- NMR and NOESY spectra as well as of their 5% Methanolic HCl degradation products. The absolute structure of the C-glycoside unit (X_3) in 1 and 2 was disclosed by applying the modified Mosher method to (S)-(-)- and (R)-(+)-MTPA esters (7 and 8) of the aglycone 6. P371A1 (1) showed a significant suppresion (percentage inhibition: ca. 61%) against pentagastrin-stimulated acid secretion, when 10mg/kg was given intraperitoneally to urethane anesthetized rats 30 min prior to the onset of pentagastrin infusion (i.v. 60μg/kg/hr). In constrast, 1 did not have any effect on acid secretory response induced by either histamine or carbachol in the experiments carried out under the same condition. Interestingly, intraperitoneal administration of 1 to unanesthetized rats 30 min prior to an oral dosage of HCl/ethanol (60% in 150mM HCl) or a subcutaneous administration of indomethacin (25mg/kg) prevented significantly and dose-dependently the lesion formation in gastric mucosa. The percentage inhibition at 1, 3 and 10mg/kg were 52.6, 81.6 and 83.6%, respectively, in the HCl/ethanol-induced lesion model and were 57.0, 64.9 and 72.8%, respectively, in the indomethacin-induced lesion model. In the binding assay, 1 was not bound to the CCK_B/gastrin receptor. Thus, 1 was presumed to hinder the gastrin from stimulating a histamine release from enterochromaffin-like (ECL) cells. Since the possibility is not ruled out that metabolites of 1 acted as a CCK_B/gastrin receptor antagonist, a further study is neccesarry to establish the definite mechanism.
天然有機化合物討論会の論文
1998-08-31

73(P49) Strestomyces sp. P371の生産する胃酸分泌抑制物質-胃粘膜保護作用を併せ持つ抗ガストリン作用物質-について(ポスター発表の部)

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