Synthesis and Biological Evaluation of Spiroketal Derivatives
| Project/Area Number |
18590027
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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 |
Chemical pharmacy
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| Research Institution | The Institute of Physical and Chemical Research |
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Principal Investigator |
TAKESHI Shimizu The Institute of Physical and Chemical Research, Synthetic Organic Chemistry, Scenior Scientist (80087569)
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| Co-Investigator(Kenkyū-buntansha) |
USUI Takeo University of Tsukuba, Graduate School of Life and Environmental Sciences, Associate Professor (60281648)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥4,020,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥420,000)
Fiscal Year 2007: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2006: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | reveromvcin A / spirofungin A / spirofuneinB / 6.6-spiroketal / bioprobe / isoleucyl-tRNA svnthetase / osteoclast / structure-activity relationship / 1,2-ジヒドロリベロマイシン / 抗生物質 |
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| Research Abstract |
Reveromycin A is a 6, 6-spiroketal antibiotic isolated from the genus Streptomyces and shows strong biological activities that makes it potentially useful as an antitumor drug based on inhibition of isoleucyl-tRNA synthetase. Reveromycin A is also expected as a therapeutic agent for hypercalcemia and bone disease. Spirofungins A and B are also polyketide-type antibiotics isolated from Streptomyces violaceusniger Tu 4113 as a mixture in the ratio of 4: 1 and show various antifungal activities, particularly against yeasts. Various derivatives of reveromycin A and spirofungin A, focusing on the 5S hydroxyl group and C18 hemisuccinyl group, were synthesized and their inhibitory effects on both the isoleucyl-tRNA synthetase activity and the survival of osteoclasts, and activities on the morphological reversion of src^<ts>-NRK cells were examined. It was found that 2, 3-dihydroreveromycin A, 4-hydrox3rreveromycin A and the 3, 5-dihydroxyl derivative are the promising derivative of reveromycin A based on the activity and stability. We have developed a novel method for the preparation of the succinates of tertiary alcohols for the synthesis of reveromycin A. 3-Butyn-1-ol was converted into a lactone in eleven steps. Oxidative cleavage of the dihydropyrans prepared via the palladium-catalyzed coupling of the ketene acetal triflates and zinc homoenolate with 0_s0_4-Pb (OAc) _4 gave the succinates of tertiary alcohols. Then, the succinates were converted into the 6, 6-spiketal via the coupling with an alkyne.
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Report
(3 results)
Research Products
(9 results)
