Design and Synthesis of New Antitumor Agents Using Marine Natural Product Lamellarin as A Structural Motif
| Project/Area Number |
18510188
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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 |
Living organism molecular science
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| Research Institution | Nagasaki University |
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Principal Investigator |
IWAO Masatomo Nagasaki University, Engineering, Professor (00100892)
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| Co-Investigator(Kenkyū-buntansha) |
FUKUDA Tsutomu Nagasaki University, Graduate School of Science and Technology, Assistant Professor (80295097)
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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 |
¥4,080,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2007: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2006: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Keywords | lamellarins / multidrug resistat(MDR) / antitumor agent / topoisomerase I inhibitor / drug design / chemical synthesis / 分子設計 / 合成 / 構造活性相関 |
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| Research Abstract |
A marine natural product lamellarin D exhibits potent cytotoxicity against a wide range of cancer cell lines. This compound is also effective for multidrug resistant (MDR)cancer cell lines. We have developed two different types of synthetic routes to lamellarine-class natural products. We have also performed structure-activity relationship studies using synthetic analogues and revealed structural requirements for cytotoxicity. Recently, Bailly and co-workers have reported that the major mechanism of action of lamellarin D is the inhibition of topoisomerase I which is known to be the molecular targent of approved camptotecin-type antitumor agents. We performed collaboration with Bailly group to propose topoisomerase I-DNA-lamellarin D ternary complex model. Based upon this model, we designed 1-dearyllammelarin D and 1-substituted 1-dearyllamellarin D as effective lamellarin D analogues. In the present research project, we planned to develop efficient synthetic routes to these analogues
… More
and evaluate their antitumor activity.
Thus, we have achieved the synthesis of 1-dearyllamellarin D in eight steps using regioselective lithiation of N-benzenesulfony1-3-bromopyrrole as a key reaction. Electrophilic substitutions of the O-protected (by isopropyl group)1-dearyllamellarin D proceeded at the 1-position selectively to give a variety of 1-substituted O-protected 1-dearyllamellarin D s. O-protected 1-bromo-1-dearyllamellarin D underwent palladium-catalyzed cross-coupling (Suzuki-Miyaura coupling)with boronic acids in the presence of CsF-Ag_2O to give the other types of 1-substituted O-protected 1-dearyllamellarin D s in good yields. Deprotection of the isopropyl group of these compounds by boron trichloride gave 1-substituted 1-dearyllamellarin D analogues.
The bioassay of these new analogues against a wide range of cancer cell lines is under investigation. A preliminary result indicated 1-dearyllamellarin D exhibited potent cytotoxicity against Hela cells in the level similar to lamellarin D. Less
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Report
(3 results)
Research Products
(25 results)
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[Journal Article] Palladium-catalyzed cross-coupling of N-benzenesulfony1-3, 4-dibromopyrrole and its application to the total syntheses of lamellarins O, P, Q, and R2008
Author(s)
T., Fukuda, E., Sudo, K., Shimokawa, M., Iwao
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Journal Title
Tetrahedron 64-2
Pages: 328-338
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Total synthesis of lamellarins D, L, and N2006
Author(s)
N., Fujikawa, T., Ohta, T., Yamaguchi, T., Fukuda, F., Ishibashi, M., Iwao
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Journal Title
Tetrahedron 62-4
Pages: 594-604
NAID
Description
「研究成果報告書概要(欧文)」より
Related Report
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