33 日本産イチイTaxus cuspidataより単離したP-糖蛋白質機能阻害作用をもつ新規タキサン化合物Taxuspine A〜E(口頭発表の部)

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Since the discovery of anticancer activity of taxol, much attention has been paid for the isolation of new taxane diterpenoids from various species of yews. In our continuing search for bioactive natural products, we examined extracts of the Japanese yew Taxus cuspidata Sieb. et Zucc. and obtained five new taxane diterpenoids, named taxuspines A〜H (1〜8) and J (9), together with known taxoids. Some of the taxoids increased cellular accumulation of vincristine in multidrug-resistant tumor cells. Here we describe isolation and structure elucidation of taxuspines A〜H (1〜8) and J (9) and the structure-activity relationships of the taxoids (1〜36). The structures of taxuspines A〜H (1〜8) and J (9) were determined by extensive analyses of ^1H-^1H COSY, HMQC, and HMBC spectra and chemical means and the relative stereochemistries of compounds 1〜5 were elucidated by NOESY spectra. Taxuspines A〜C (1〜3), H (8), and J (9) possess different skeletons from usual taxoids consisting a 6/8/6-membered ring system. Taxuspines A (1) and J (9) is a rare example of taxoids involving of a 5/7/6-membered ring system, of which the skeleton has been recently reported for taxchinins. Taxuspine B (2) is the second example of taxane diterpenoid involving a 6/10/6-membered ring system. On the other hand, taxuspines C (3) and H (8) possesses an unusual 6/5/5/6-membered ring system. Taxuspine D (4) is the first taxane diterpenoid containing an enoleacetate moiety. Some of the taxoids (2,3,9,14,15,17,18, and 36) increased the vincristine accumulation in multidrug-resistant tumor 2780AD cells as potent as verapamil, while taxol (26) decreased the vincristine accumulation in the cells. These results imply that the taxoids could be substrates of P-glycoprotein and useful for overcoming of multidrug-resistance. Taxuspine D (4) exhibited taxol-like activity to inhibit markedly Ca^<2+>-induced depolymerization of microtubules, although it lacks the oxetane ring and N-acylphenylisoserine moiety which are often associated with unique activity of taxol (26). It is noted that taxuspine E (5) lacking the side chain at C-13 showed potent cytotoxicity against KB cells, since the baccatin III-type compounds having an oxetane ring but no C-13 side chain were reported to be ca. 1700-fold less cytotoxic against KB cells than taxol (26).
天然有機化合物討論会の論文
1995-09-01

33 日本産イチイTaxus cuspidataより単離したP-糖蛋白質機能阻害作用をもつ新規タキサン化合物Taxuspine A〜E(口頭発表の部)

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