| Co-Investigator(Kenkyū-buntansha) |
TSUDA Masashi Hokkaido Univ., Grad.School of Pharm.Sci., Associate Professor, 大学院・薬学研究科, 助教授 (10261322)
KUBOTA Takaaki Hokkaido Univ., Grad.School of Pharm.Sci., Lecturer, 大学院・薬学研究科, 講師 (60399954)
ISHIYAMA Haruaki Hokkaido Univ., Grad.School of Pharm.Sci., Research Asistant, 大学院・薬学研究科, 助手 (70333622)
森田 博史 北海道大学, 大学院・薬学研究科, 助教授 (70220069)
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| Budget Amount *help |
¥13,500,000 (Direct Cost: ¥13,500,000)
Fiscal Year 2005: ¥5,700,000 (Direct Cost: ¥5,700,000)
Fiscal Year 2004: ¥7,800,000 (Direct Cost: ¥7,800,000)
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| Research Abstract |
1)Eight stilbenoids, 1-(p-hydroxybenzyl)-4,8-dimethoxyphenanthrene-2,7-diol (1), 2,7-dihydroxy-1,3-bis(p-hydroxybenzyl)-4-methoxy-9,10-dihydrophenanthrene (2), 4,7-dihydroxy-1-(p-hydroxyberzyl)-2-methoxy-9,10-dihydrophenanthrene (3), 3,3'-dihydroxy- 2',6'-bis(p-hydroxybenzyl)-5-methoxybibenzyl (4), 3',5-dihydroxy-2-(p-hydroxybenzyl)-3-methoxybibenzyl (5), blestriarenes B (6) and C (7), and blestrianol A (8) have been isolated by the guidance of inhibitory effect of tubulin polymerization from the tubers of Bletilla striata (Orchidaceae). Among them, 4 and 5 inhibited the polymerization of tubulin at IC_<50> 10 μM, respectively. Furthermore 4 potentiated the cytotoxicity of SN-38 in BCRP-transduced K562 (K562/BCRP) cells.
2)3D QSAR of rhazinilam (9), an alkaloid isolated from Rhazya stricta (Apocynaceae) with an activity involving disassembly of microtubules and its derivatives, was investigated by using the comparative molecular field analysis (CoMFA). In an effort to get a better under
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standing of the correlation between conformation and antitubulin activity of 9, most probable minimum energy conformation in solution of 9 was analyzed on the basis of NMR data of 9 in solution. The results indicated a correlation between the antitubulin activity of these alkaloids and the steric and electrostatic factors, which modulate their biological activity, and accounted for the potent activities of 9 with suitable relationship for the overall conformation.
3)Solution conformations of amphidinolide H(10), a 26-membered macrolide exhibiting potent cytotoxic and antitumor activity, in CDCl_3 and DMSO-d_6 were investigated on the basis of NMR data, distance geometry calculation, and restrained energy minimization. Three-dimensional conformations in CDCl_3 were suggested to be close to the X-ray structure of 10, while those in DMSO-d_6 were indicated to be different from both those in CDCl_3 and the X-ray structure.
4)Two new cytotoxic 26-membered macrolides, amphidinolides B4(11) and B5(12), have been isolated from a marine dinoflagellate Amphidinium sp.(strain Y-100), and the structures were elucidated on the basis of detailed analyses of 2D NMR data including 13C- 13C correlations. Less
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