32 有糸分裂阻害剤の構造と活性及びチューブリン上の結合部位に関する研究(口頭発表の部)

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Sites of action of anti-mitotic compounds to tubulin has been classed to two sites; colchicine site and vinblasitne/maytansine site. In our study on interaction between tubulin and rhizoxin, a potent spindle poison, it was suggested that rhizoxin binds to the maytansine site, the third site, different from those for colchicine and vinblastine. In our present study, we attempted modification of rhizoxin and 20-demethoxy-20-hydroxy-ansamitocin P-3 (2c, a maytansinoid compound) for the purpose of constructing the photo-affinity probe for the rhizoxin/maytansine site. Rhizoxin was converted to 20,21-seco-20-al (7) by successive OsO_4 and NaIO_4 treatments, and the aldehyde 7 was reduced with NaBH_3CN to give 20,21-seco-20-01 (8). The compounds 7 and 8 were transformed to a variety of derivatives with modified side chains, 7a-f and 8a-i respectively. Their biological activity was tested. Inhibition of tubulin polymerization by the Wittig reaction products 7a-f were as strong as rhizoxin, whereas such activity of the 20-ol-acylates 8a-i was much weaker. 20-Demethoxy-20-hydroxy-ansamitocin P-3 (2c) was converted to a vriety of 20-ol acylates 9a-f. Their inhibiton of tubulin polymerization were as potent as ansamitocin P-3. In addition, the binding of [^<14>C]20-demethoxy-20-p-azido-benzoyloxy-ansamitocin P-3 (9f) was shown to be competitive to ansamitocin P-3 (2b) and rhizoxin (1). The compound 9f was thus selected as the first photo-affinity probe for the rhizoxin/maytansine site.
天然有機化合物討論会の論文
1989-09-17

32 有糸分裂阻害剤の構造と活性及びチューブリン上の結合部位に関する研究(口頭発表の部)

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