音松 俊彦 神戸天然物化学(株), チームリーダー(研究職)
平田 直則 神戸天然物化学(株), 開発部長(研究職)
SUZUKI Todshio NIIGATA UNIVERSITY, Faculty of Engineering, Professor, 工学部, 教授 (80202133)
OTOMATSU Toshihiko Kobe Natural Products & Chemiclas Co., Lts., Team Leader, Research & Development Dept.
HIRATA Naonori Kobe Natural Products & Chemicals Co., Ltd., manager, Research & Development Dept.
|Budget Amount *help
¥12,100,000 (Direct Cost : ¥12,100,000)
Fiscal Year 2000 : ¥1,700,000 (Direct Cost : ¥1,700,000)
Fiscal Year 1999 : ¥2,000,000 (Direct Cost : ¥2,000,000)
Fiscal Year 1998 : ¥8,400,000 (Direct Cost : ¥8,400,000)
(1) Taxol, Taxol analogs, and New Basic and Neutral Taxoids from Taxus cuspidata
(a) We examined the content of taxol in needles and stems of Japanese yew, Taxuscuspidata grown in different 5 places in Japan, Sendai, Matumoto, Wakkanai, Asahikawa, and Toyotomi. The isolated yields of taxol are 0.0022%, 0.0006%, 0.0043%, 0.0033%, 0.0007% based on the weight of fresh needles and stems respectively. The results show that 25 Kg of fresh reproducible needles and stems of T. cuspidata grown in Wakkanai, produce 1 g of taxol. We also isolated new basic and neutral taxoids and determined their structures mainly by spectroscopic method.
(b) We examined biological activity of 42 taxoids as modulators of multidrug resistant cancer cells and found that 11 taxoids showed strong activity. In them taxinines NN-1 and NN-11 also showd anticancer activity in the screening assay by cell line panel, the results of which suggest that they are a new type of anticancer reagent.
(2) Production of Taxol, Taxol an
alogs, Taxuyunnanine C and Its Related Compounds by Callus Culture of T. cuspidata. The Callus cultures induced from young stems of T. cuspidata grown in Sendai produce twxol, and 14 taxoids including 6 taxol analogs. The yield of taxol is 263 mg/1 Kg dry callus and the total yield of taxoids is 16.6 g/1 Kg dry callus. In them 5 kinds of taxoids, which are produced in excellent yields in callus cultures but not produced in the needles and stems, showed high activity as the modulator of multidrug resistant cancer cell. the yields and the kinds of products largely depend on additives and conditions.
(3)Partial Synthesis of Biologically, Active Taxoids. Since the very limited amount of biologically active taxinines NN-1, -3, -7, -14, and 5-cinnamoyl-10-acetoxy taxcin II were produced from natural sources, they were synthesized from taxinine, which is the most abundant product in needles and young stems of T. cuspidata, in good yoilds to keep enough amount of samples in vivo assay of these compounds. Less