1995 Fiscal Year Annual Research Report

水圏生物からの抗腫瘍リ-ド化合物の開発と創製

Research Project

Project/Area Number	07274104
Research Institution	The University of Tokyo
Principal Investigator	伏谷伸宏東京大学, 農学部, 教授 (70012010)
Co-Investigator(Kenkyū-buntansha)	比嘉辰雄琉球大学, 理学部, 教授 (10101461) 沼田敦大阪薬科大学, 薬学部, 教授 (50067279) 小林資正大阪大学, 薬学部, 教授 (40116033) 上村大輔静岡大学, 理学部, 教授 (00022731) 山田泰司東京薬科大学, 薬学部, 教授 (10057317)
Keywords	抗腫瘍物質 / リ-ド化合物 / 細胞毒性 / 海洋生物 / 海綿 / ホヤ / 海洋細菌 / 海藻
Research Abstract	海綿を中心とした海洋無脊椎動物から細胞毒性物質の探索を行い、60に及ぶ活性物質を単離・構造決定することができた。これらのうち、沖縄産海綿2種から得られた新規マクロリドのneolaulimalideとzampanolideはP388白血病細胞に大してそれぞれIC_<50>0.05および0.001μg/mLの細胞毒性を示した。八重山産海綿Xestospongia sp.からは、aragusterolの新規誘導体が3種得られたが、活性はあまり強くなかった。先に報告した群体ホヤ由来のステロイド二量体のritterazine A-Cに加え新規誘導体23種が得られ、最も活性の強かったritterazine Bの構造変換から得られた知見とともに、ある程度の構造一活性相関が明らかとなった。なお、沖縄産のハボウキガイから強い細胞毒性をもつ特異なアルカロイドが分離された。海綿から得られた有望化合物のaragusterol類についてより有効な誘導体の検討を行っているが、デオキシコール酸を出発原料として合成したaragusterolと胆汁酸のハイブリッド化合物が、KB細胞に対して強い細胞毒性を示した。また、arenastatin Aの改良合成法の確立とアナログの合成により、構造一活性相関に関する知見が得られた。大型海藻から、ジテルペンを主とする細胞毒性物質が12種得られた。一方、海洋微生物から多くの細胞毒性物質が得られているが、なかでも巻き貝から分離された細菌から発見されたhomocereurideはP388細胞に対してIC_<50>0.0014ng/mLと非常に強い活性を示し、今後の展開が注目される。海藻から分離された細菌から得られたleptosin類も顕著は活性を示した。また、がん転移阻害物質の検索をVCAM-1を用いて行い、数種の活性物質を発見した。

Research Products
(16 results)

All Other

All Publications (16 results)

[Publications] H. Li: "Halicylindramides A-C, antifungal and cytotoxic depsipeptides from the marine Sponge Halichondria cylindrata." J. Med. Chem.38. 338-343 (1995)
[Publications] S. Fukuzawa: "Isolation and structure elucidation of ritterazines B and C, highly cytotoxic steroidal alkaloids, from the tunicate Ritterella tokioka." J. Org. Chem.60. 608-614 (1995)
[Publications] S. Matsunaga: "Theonellamides A-E, cytotoxic bicyclic peptides, from a marine sponge Theonella sp." J. Org. Chem.60. 1177-1181 (1995)
[Publications] H. Li: "Halicylindrosides, antifungal and cytotoxic cerebrosides from the marine Sponge Halichondria cylindrata." Tetrahedron. 51. 2273-2280 (1995)
[Publications] S. Fukuzawa: "Ten more ritterazines, cytotoxic steroidal alkaloids from the tunicate Ritterella tokioka." Tetrahedron. 51. 6707-6716 (1995)
[Publications] H. Mitome: "Synthesis of antitumor marine steroid aragusterols." Tetrahedron Lett.36. 8231-8234 (1995)
[Publications] G. Y. S. Wang: "Homocereulide, an extremely potent cytotoxic depsipeptide from the marine bacterium Bacillus cereus." Chem. Lett.791-792 (1995)
[Publications] M. Kobayashi: "Four new β-carboline alkaloids isolated from two Okinawan marine sponges of Xestospongia sp. and Haliclona sp." Tetrahedron. 51. 3727-3736 (1995)
[Publications] M. Kobayashi: "Improved total synthesis and structure-activity relationship of arenastatin A, a potent cytotoxic spongean depsipeptide." Chem. Pharm. Bull.43. 1598-1600 (1995)
[Publications] C. Takahashi: "Cytotoxic metabolites from a fungal adherent of a marine alga." Phytochemistry. 38. 155-158 (1995)
[Publications] C. Takahashi: "Potent cytotoxic metabolites from a Leptosphaeria spesies. Structure determination and conformational analysis." Tetrahedron. 51. 3483-3498 (1995)
[Publications] C. Takahashi: "Fumiquinazolines A-G, novel metabolites of a fungus separated from a Pseudolabrus marine fish." J. Chem. Soc. Perkin Trans.1. 2345-2353 (1995)
[Publications] Y. Nagai: "New chiral anisotropic reagents for determining the absolute configulation of carboxylic acids." Tetrahedron Lett.36. 1853-1856 (1995)
[Publications] C. W. Jefford: "Structures and absolute configulations of the marine toxins,latrunculin A and laulimalide." Tetrahedron Lett.37. 159-162 (1995)
[Publications] T. Higa: "Importance of coral reef organisms in the search for new biologically active substances." Asian Fisheries Society Special Publication. No. 10. 207-216 (1995)
[Publications] T. Higa: "Bioactive compounds from marine invertebrates." Proc. Int. Symp. Ciguatera Marine Natural Products. 251-262 (1995)

1995 Fiscal Year Annual Research Report

水圏生物からの抗腫瘍リ-ド化合物の開発と創製

Principal Investigator

伏谷 伸宏 東京大学, 農学部, 教授 (70012010)

Research Products

[Publications] H. Li: "Halicylindramides A-C, antifungal and cytotoxic depsipeptides from the marine Sponge Halichondria cylindrata." J. Med. Chem.38. 338-343 (1995)

[Publications] S. Fukuzawa: "Isolation and structure elucidation of ritterazines B and C, highly cytotoxic steroidal alkaloids, from the tunicate Ritterella tokioka." J. Org. Chem.60. 608-614 (1995)

[Publications] S. Matsunaga: "Theonellamides A-E, cytotoxic bicyclic peptides, from a marine sponge Theonella sp." J. Org. Chem.60. 1177-1181 (1995)

[Publications] H. Li: "Halicylindrosides, antifungal and cytotoxic cerebrosides from the marine Sponge Halichondria cylindrata." Tetrahedron. 51. 2273-2280 (1995)

[Publications] S. Fukuzawa: "Ten more ritterazines, cytotoxic steroidal alkaloids from the tunicate Ritterella tokioka." Tetrahedron. 51. 6707-6716 (1995)

[Publications] H. Mitome: "Synthesis of antitumor marine steroid aragusterols." Tetrahedron Lett.36. 8231-8234 (1995)

[Publications] G. Y. S. Wang: "Homocereulide, an extremely potent cytotoxic depsipeptide from the marine bacterium Bacillus cereus." Chem. Lett.791-792 (1995)

[Publications] M. Kobayashi: "Four new β-carboline alkaloids isolated from two Okinawan marine sponges of Xestospongia sp. and Haliclona sp." Tetrahedron. 51. 3727-3736 (1995)

[Publications] M. Kobayashi: "Improved total synthesis and structure-activity relationship of arenastatin A, a potent cytotoxic spongean depsipeptide." Chem. Pharm. Bull.43. 1598-1600 (1995)

[Publications] C. Takahashi: "Cytotoxic metabolites from a fungal adherent of a marine alga." Phytochemistry. 38. 155-158 (1995)

[Publications] C. Takahashi: "Potent cytotoxic metabolites from a Leptosphaeria spesies. Structure determination and conformational analysis." Tetrahedron. 51. 3483-3498 (1995)

[Publications] C. Takahashi: "Fumiquinazolines A-G, novel metabolites of a fungus separated from a Pseudolabrus marine fish." J. Chem. Soc. Perkin Trans.1. 2345-2353 (1995)

[Publications] Y. Nagai: "New chiral anisotropic reagents for determining the absolute configulation of carboxylic acids." Tetrahedron Lett.36. 1853-1856 (1995)

[Publications] C. W. Jefford: "Structures and absolute configulations of the marine toxins,latrunculin A and laulimalide." Tetrahedron Lett.37. 159-162 (1995)

[Publications] T. Higa: "Importance of coral reef organisms in the search for new biologically active substances." Asian Fisheries Society Special Publication. No. 10. 207-216 (1995)

[Publications] T. Higa: "Bioactive compounds from marine invertebrates." Proc. Int. Symp. Ciguatera Marine Natural Products. 251-262 (1995)

伏谷伸宏東京大学, 農学部, 教授 (70012010)