水圏生物からの抗腫瘍リ-ド化合物の開発と創製

• Project/Area Number: 06282106
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• 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) ; 楠見 武徳 徳島大学, 薬学部, 教授 (70015882) ; 小林 資正 大阪大学, 薬学部, 助教授 (40116033) ; 上村 大輔 静岡大学, 教養部, 教授 (00022731) ; 山田 泰司 東京薬科大学, 薬学部, 教授 (10057317)
• Project Period (FY): 1994
• Project Status: Completed (Fiscal Year 1994)
• Budget Amount: ¥14,700,000 (Direct Cost: ¥14,700,000); Fiscal Year 1994: ¥14,700,000 (Direct Cost: ¥14,700,000)
• Keywords: 海綿 / 群体ホヤ / 海洋細菌 / 細胞毒性 / 抗腫瘍性 / ステロイド / デプシペプチド / マクロリド

Research Abstract

先ず,日本各地で海綿を中心とする海洋無脊椎動物および海藻を採集し,腫瘍細胞に対する増殖阻害活性を指標に活性物質の探索を行ったところ,テルペン,アルカロイド,マクロリド,ペプチドなど広範な化合物が含まれる40に及ぶ細胞毒性物質が得られた.これらのうち,伊豆半島産群体ホヤRitterella tokiokaから得られたステロイド二量体アルカロイドritterazineA-C,石垣島産海綿Xestospongia sp.由来のステロイドaragusterolA-D,沖縄産海綿Hyrtios altumから分離された特異マクロリドaltohyrtin類,および西表島産海綿Dysidea arenariaから発見されたデプシペプチドarenastatin Aは,いずれも著しい細胞毒性を示し,リ-ド化合物として期待される.さらに,aragusterol AとCは,有望な抗腫瘍性(1.6mg/kgの投与で,T/C>220%)を示したので,aragusterol類の相互変換と誘導体の作製を試みた結果、aragusterol Aの3β還元体も強い活性を持つことがわかった.また,arenastatin Aの全合成も達成さ,より有効なリ-ド化合物の創製に取り組んでいる.一方,海洋生物から分離した海洋細菌を対象とした探索においても,アルカロイド,マクロリド,ペプチドなどの様々な細胞毒性を示す化合物が得られた.なかでも伊豆半島産巻貝から分離したバクテリアから得られたデプシペプチドhomocerulideは,強力な細胞毒性を示し,今後の展開が期待される.

Research Products

• [Publications] H.Shimura et al.: "Aragusterol C:a novel halogenated marine sterol from an Okinawan sponge,Xestospongia sp.,possessing potent anttcumor activity." Experientia. 50. 134-136 (1994)
• [Publications] K.Iguchi et al.: "Aragusterol B and D,new 26,27-cyclosterols from the Okinawan marine sponge of the genus Xestospongia." J.Org.Chem.59. 7499-7502 (1994)
• [Publications] M.Kobayashi et al.: "Structure-activity correlation of a potent cytotoxic dimeric macrolide swinholide A,from the Okinawan marine sponge Theonella swinhoei,and its isomers." Chem.Pharm.Bull.42. 19-26 (1994)
• [Publications] M.Kobayashi et al.: "Absolute configulations of C-4 of the manoalide family,biologically active sesterterpenes from the marine sponge Hyrtios erecta." Chem.Pharm.Bull.42. 265-270 (1994)
• [Publications] M.Kobayashi et al.: "Absolute stereostructure of altohyrtin A and its congeners,potent cytotoxic macrolides from the Okinawan marine sponge Hyrtios altum." Tetrahedron Lett.35. 1243-1246 (1994)
• [Publications] M.Kobayashi et al.: "Arenastatin A,a potent cytotoxic depsipeptide from the Okinawan marine sponge Dysidea arenaria." Tetrahedron Lett.35. 7969-7972 (1994)
• [Publications] M.Kobayashi et al.: "The absolute stereostructure of arenastatin A,a potent cytotoxic depsipeptide from the Okinawan sponge Dysidea arenaria." Chem.Pharm.Bull.42. 2196-2198 (1994)
• [Publications] M.Kobayashi et al.: "A total synthesis of arenastatin A,an extremely potent cytotoxic depsipeptide,from the Okinawan marine sponge Dysidea arenaria." Chem.Pharm.Bull.42. 2394-2396 (1994)
• [Publications] J.M.Oclarit et al.: "Anti-bacillus substance in the marine sponge,Hyatella species,produced by an associated Vibrio species bacterium." Microbios. 78. 1-16 (1994)
• [Publications] J.M.Oclarit et al.: "A novel antimicrobial substance from a strain of the bacterium,Vibrio sp." Nat.Prod.Lett.4. 309-312 (1994)
• [Publications] J.Tanaka et al.: "Helioxenicins A-C:diterpenes from the blue coral Heliopora coerulea." Tetrahedron. 50. 9989-9996 (1994)
• [Publications] M.Tsuda et al.: "Four new cyclic octapeptides from the Okinawan marine sponge Hymeniacidon sp." Tetrahedron. 50. 4667-4680 (1994)
• [Publications] T.Hamada et al.: "Polytheonamides,unprecedented highly cytotoxic polypeptides,from the marine sponge Theonella swinhoei.I.Isolation and component amino acids." Tetrahedron Lett.35. 719-720 (1994)
• [Publications] T.Hamada et al.: "Polytheonamides,unprecedented highly cytotoxic polypeptides,from the marine sponge Theonella swinhoei.2.Structure elucidation." Tetrahedron Lett.35. 609-612 (1994)
• [Publications] G.Ryu et al.: "Discodermin F,a cytotoxic and antimicrobial tetradecapeptide,from the marine sponge Discodermia kiiensis." Tetrahedron Lett.35. 8251-8254 (1994)
• [Publications] S.Fukuzawa et al.: "Ritterazine A,a highly cytotoxic dimeric steroidal alkaloid,from the tunicate Ritterella tokioka." J.Org.Chem.59. 6164-6166 (1994)
• [Publications] G.Ryu et al.: "Discodermins F-H,cytotoxic and antimicrobial tetradecapeptides,from the marine sponge Discodermia kiiensis:structure revision of discodermins A-D.21GC17:Tetrahedron" 50. 13409-13416 (1994)
• [Publications] S.Fukuzawa et al.: "Isolation and structure elucidation of ritterazines B and C,highly cytotoxic dimeric steroidal alkaloids,from the tunicate Ritterella tokioka." J.Org.Chem. 60(印刷中). (1995)