| Project/Area Number |
07307022
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Chemical pharmacy
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| Research Institution | HOKKAIDO UNIVERSITY |
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Principal Investigator |
KOBAYASHI Jun'ichi Hokkaido Univ., Fac.Pharmaceutical Sciences, Professor, 薬学部, 教授 (90221241)
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| Co-Investigator(Kenkyū-buntansha) |
YAMAMURA Shosuke Keio Univ., Fac.Science and Technology, Prof., 理工学部, 教授 (40076708)
FUJI Kaoru Kyoto Univ., Institute of Chemical Research, Professor, 化学研究所, 教授 (20027056)
TSURUO Takashi The Univ.of Tokyo, Institute of Molecular and Cellular Biosciences, Professor, 分子細胞生物学研究所, 教授 (00012667)
IWASAKI Shigeo The Kitasato Institute, Head director, 生物機能研究所, 部長 (00013326)
ITOKAWA Hideji Tokyo Univ.Pharmaceutical and Life Science, Professor, 薬学部, 教授 (60057304)
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| Project Period (FY) |
1995 – 1997
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| Project Status |
Completed (Fiscal Year 1997)
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| Budget Amount *help |
¥22,600,000 (Direct Cost: ¥22,600,000)
Fiscal Year 1997: ¥6,100,000 (Direct Cost: ¥6,100,000)
Fiscal Year 1996: ¥8,000,000 (Direct Cost: ¥8,000,000)
Fiscal Year 1995: ¥8,500,000 (Direct Cost: ¥8,500,000)
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| Keywords | natural products / multidrug-resistance / P-glycoprotein / antitumor / tubulin / mechanism of MDR / MDR modifier / MRSA |
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| Research Abstract |
In this research project, we have investigated on search and development for new compounds to overcome drug resisiance from natural sources.
1) From the Japanese yew Taxus cuspidata and the Chinese yew Taxus chinensis, new taxoids and related diterpenoids were isolated and the structures elucidated on the basis of spectroscopic data and chemical means. Some taxoids increased accumulation. of vincristine in multidrug-resistant cells and inhibited binding of azidopine to P-glycoprotein. Taxuspine C enhanced the chemotherapeufic effect of anticancer agent in vivo.2) A structure-activity relationship study RA-related cyclic peptides revealed that RA-VII showed the most potent antitumor activity. RA-VII is under a clinical phase I trial.3) Total synthesis of curacin A,a novel antimitotic agent isolated from a Caribbean cyanobacterium, and studies on the structure-activity relationships of ustiloxin D,antimitotic-cyclic peptidc produced by the rice plant pathogen, were carried out.4) Some new bioactive compounds which reversed multidrug resistance were isolated from actinomycetes and plants.5) MS-209 is a novel quinoline compound which can overcome multidrug resistance both in vitro and in vivo and is being evaluated in a clinical phase II study. We found that MDR reversal activity of PSC833, an analogue of cyclosporin A,was potentiated by MRK-16.6) Ribosylation by mycobacterial strains as a new mechanism of rifampin inactivation was found and these inactivated metabolites were isolated and the structures were determined.7) Seco-aglucovancomycins were synthesized by means of TTN oxidation as a key step. We found that interaction between bacterial cell wall model and these seco-aglucovancomycins consisted of hydrogen bondings and molecular shape fittings. Total synthesis of hapalosin, a cyclic peptide possessing multidrug resistance reversing activities was accomplished.
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