51(P-21) 放線菌由来新規2',5'-ホスホジエステラーゼ阻害物質A-74528(ポスター発表の部)

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The 2-5A system is one of the major pathways involved in anti-viral function that can be induced by interferons (IFNs). The 2-5A is synthesized with several specific enzymes and binds and activates RNaseL which in turn degrades viral and cellular RNAs and thereby shuts off the protein synthesis in virus-infected cells. The action of 2-5A is transient however, and it is immediately deactivated by 2',5' - specific phosphodiesterase (2'-PDE). Therefore, it was considered that we might have an anti-viral effect if the half-life of 2-5A were prolonged by in hibiting 2'-PDE. Based upon the background, we performed screening of 2'-PDE inhibitors in microbial extracts and found A-74528 (1) in the culture broth of Streptomyces sp. SANK 61196. The planar structure of 1, C_<30>H_<24>O_<11> ([M+H]^+, m/z 561.1405 Δ +0.8mmu), was mainly elucidated by NMR techniques including natural abundance INADEQUATE, to be a highly fused polyketide as shown in Fig. 1-3. The relative configuration and the conformation of 1 were elucidated by the analysis of NOEs and assessment of dihedral angles predicted by QUANTA/CHARMm-computations and coupling constants (Fig. 4-5 and Table 2). In that model, ring A, B, and C, and ring D, E, and F, are roughly in the same planes, which are connected at angles of about 90° and α-pyrone moiety extends on top of a "roof' consisting of two planes. 1 inhibits partial purified bovine 2'-PDE with IC_<50> of 2.3μg/ml and purified recombinant human 2'-PDE with IC_<50> of 34μg/ml, which we recently identified and cloned.
天然有機化合物討論会の論文
2004-10-01

51(P-21) 放線菌由来新規2',5'-ホスホジエステラーゼ阻害物質A-74528(ポスター発表の部)

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