2011 Fiscal Year Final Research Report
Elucidation and Control of the Molecular Mechanism of Action of the Multifunctional Antitumor Agents Lamellarins
| Project/Area Number |
20310135
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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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 長崎大学, 大学院・工学研究科, 教授 (00100892)
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| Co-Investigator(Kenkyū-buntansha) |
ISHIBASHI Fumito 長崎大学, 大学院・水産・環境科学総合研究科, 教授 (10192486)
FUKUDA Tsutomu 長崎大学, 大学院・工学研究科, 助教 (80295097)
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| Project Period (FY) |
2008 – 2011
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| Keywords | ラメラリン / 抗がん剤 / トポイソメラーゼI / プロテインキナーゼ / 選択的阻害剤 / 構造活性相関 / ドッキングシミュレーション / 活性発現分子機構 |
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| Research Abstract |
Marine natural products lamellarins are the multifunctional antitumor agents which inhibit both topoisomerase I and protein kinases(CDKs, GSK-3, Pim1, DYRK1A, CLKs, etc). In this research, we intended to produce target-selective inhibitors through SAR and docking simulation studies. As the results, we established following new facts. The kinase-selective(or topo I-selective) inhibitors can be produced by proper arrangement of the peripheral oxygen functionalities(OH or OMe) on the lamellarin skeleton. The inhibitory activity and selectivity of two enantiomers of 16-methyllamellarin N, which are generated by restricted rotation around C1-C11 single bond, on the protein kinases are quite different. The lamellarin N analogues having a substituent at C1 instead of an aromatic ring exhibited good selectivity on the protein kinases depending on the structure of C1-substituent.
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