| Project/Area Number |
14580615
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Bioorganic chemistry
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| Research Institution | OSAKA CITY UNIVERSITY |
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Principal Investigator |
USUKI Yoshinosuke OSAKA CITY UNIVERSITY, GRADUATE SCHOOL OF SCIENCE, LECTURER, 大学院・理学研究科, 講師 (30244651)
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| Co-Investigator(Kenkyū-buntansha) |
TANIGUCHI Makoto OSAKA CITY UNIVERSITY, GRADUATE SCHOOL OF SCIENCE, PROFESSOR, 大学院・理学研究科, 教授 (00047309)
FUJITA Ken-ichi OSAKA CITY UNIVERSITY, GRADUATE SCHOOL OF SCIENCE, LECTURER, 大学院・理学研究科, 講師 (10285281)
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| Project Period (FY) |
2002 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2003: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2002: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | structure-activity relationship / antifungal activity / respiratory inhibition / 9-membered dilactone / 活性酸素種 |
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| Research Abstract |
UK-2A is a novel antifungal antibiotic isolated from Streptomyces sp. 517-02, and is similar to antimycin A3 (AA) in both structure, and inhibitory activity towards electron transport at complex III in mitochondria. However, UK-2A was less cytotoxic than AA in several mammalian cell lines. Because both UK-2A and AA inhibited mitochondrial electron transport, the difference in cytotoxicity could be attributed to differences in production of reactive oxygen species (ROS), accounting for the mechanism of the low cytotoxcity of UK-2A, which is its most prominent effect characteristic.
In our studies into establishing structure-activity relationships among UK-2A analogues, a series of hybrid molecules combining structural features of both UK-2A and AA were synthesized to evaluate the inhibitory activity for the uncoupler stimulated respiration of bovine heart SMP and the cytotoxic activity. A hybrid, which was prepared with the 9-membered dilactone residue of UK-2A and the 3-formylaminosalic
… More
ylic moiety of AA, showed the respiratory inhibition as much as UK-2A or AA and demonstrated also some extent of low cytotoxcity as UK-2A. Preliminary studies on the application of these hybrids for agricultural chemicals were carried out.
Other analogous compounds in which the nine-membered dilactone residue was replaced with several alkyl or isoprenyl moieties were prepared. C9-UK-2A, substituted the dilactone ring of UK-2A with n-nonyl moiety, showed the most potent and durable antifungal activities among these derivatives. It's mode of action against two yeasts, Rhodotorula mucilaginosa IFO 0001(RM) and Saccharomyces cerevisiae IFO 0203 (SC) was examined. C9-UK-2A demonstrated a cidal effect to the growth inhibition of RM with membrane injury. On the other hand, C9-UK-2A inhibited the respiration and induced the production of ROS in whole cells as well as intact mitochondria of SC. The growth inhibition of SC induced by C9-UK-2A would depend on the oxidative stress caused by excessive ROS production. Less
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