1990 Fiscal Year Annual Research Report

天然物由来制癌物質の探索とその化学的誘導に関する研究

Research Project

Project/Area Number	02151018
Research Institution	The University of Tokyo
Principal Investigator	瀬戸治男東京大学, 応用微生物研究所, 教授 (10013335)
Co-Investigator(Kenkyū-buntansha)	長田裕之理化学研究所, 研究員 (80160836) 長尾善光徳島大学, 薬学部, 教授 (40027074) 岩崎成夫東京大学, 応用微生物研究所, 教授 (00013326) 別府輝彦東京大学, 農学部, 教授 (80011873) 大岳望帝京大学, 理工学部, 教授 (30013303)
Keywords	ベントシアニン / リベロマイシン / カプラマイシン誘導体 / ヒストンデアセチラ-ゼ阻害剤 / リゾキシンアシル誘導体 / カンプトテシンアシル誘導体 / 多剤耐性克服機構 / 抗癌抗生物質
Research Abstract	本年度の各班員の研究実績は以下のとおりである。(瀬戸)癌細胞に有効な物質を検索し、放線菌の培養液から新規化合物ベントシアニンAを単離しその構造を決定した。本化合物はフェナジン系の化合物でP388に活性を示した。また新規抗癌剤抗生物質としてシトロペプチンとバリアペプチンを単離し、その構造を決定した。(大岳)ヌクレオシド系抗生物質の化学変換を行ない、アングストマイシンCおよびカプラマイシンの種々のデオキシ誘導体を調製し、活性の高い化合物を得た。(別府)細胞周期特異的に作用する物質の検索を行ない、放線菌の培養液から新規化合物を得、その構造をレプトマイシンのデメチル誘導体であると決定した。また、トリコスタチンAがヒストンデアセチラ-ゼを強力に阻害することを明らかにした。(岩崎)強い細胞毒性を持つリゾキシンの誘導体を合成し、その作用を検討したところ、13位のアシルエステル誘導体が優れた抗腫瘍活性を示すことが明かとなった。特にパルミチン酸エステル体は、各種固形癌に高い効果を示し、臨床試験に移行中である。(鶴尾)新規抗癌剤であるモルホリノアンスラサイクリンであるMXー2が多剤耐性細胞に有効性を示す機構について研究を行ない、その結果、耐性細胞への取込が良いこと、その取込はアドリアマイシンに比べて10倍以上早いこと、抗癌剤排出ポンプであるPー糖蛋白質に親和性のあることを明らかにした。(長尾)カンプトテシンの20位の種々のアシル誘導体を調製してその活性を検討し、炭素数の18カルボン酸誘導体が優れた活性を示すこと、20位の立体が活性の発現に極めて重要であることを見出した。(長田)上皮増殖因子のマイトジェン活性を阻害する物質をスクリ-ニングした結果、新規抗生物質リベロマイシンを単離し、その構造を決定した。本物質は細胞周期の進行を阻害することが明かとなった。またHLー60やKー562等のヒト由来癌細胞に強い活性を示した。

Research Products

(17 results)

All Other

All Publications (17 results)

[Publications] T.Kawano: "Isolation and structures of new chromomycin antibiotics 02ー3D and 02ー3G from <Sreptomyce>___ーs <avellaneus>___ー." J.Antibiotics. 43. 110-113 (1990)
[Publications] M.Nakagawa: "A new depsipeptide antibiotic,variapeptin." Agric.Biol.Chem.54. 791-794 (1990)
[Publications] Y.Hayakawa: "A new depsipeptide antibiotic,citropeptin." Agric.Biol.Chem.54. 1007-1011 (1990)
[Publications] M.Nakagawa: "Structural studies on new depsipeptide antibiotics,variapeptin and citropeptin." J.Antibiotics. 43. 477-484 (1990)
[Publications] K.Shinーya: "The structure of benthocyanin A.A new free radical scavenger of microbial origin." Tetrahedron Lett.32. 943-946 (1990)
[Publications] K.Kakinuma: "Intramolecular stacking of gilvocarcin V:Tetraacetate as evidenced by NMR studies." J.Antibiot.43. 1077-1081 (1990)
[Publications] M.Yoshida: "Potent and specific inhibition of mammalian histone deacetylase both <in>___ー <vivo>___ー and <in>___ー <vitro>___ー by trichostatin A." J.Biol.Chem.265. 17174-17179 (1990)
[Publications] K.Abe: "Highly synchronous culture of fibroblasts from G2 block caused by staurosporine,a potent inhibitor of protein kinases." Exper.Cell Research. 192. 122-127 (1991)
[Publications] Y.Kato: "Studies on macrocyclic lactone antibiotics XIII.Antiーtubulin activity and cytotoxicity of rhizoxin derivatives:Synthesis of a photoaffinity derivative." J.Antibiotics. 44. 66-75 (1991)
[Publications] A.S.Sullivan: "Interaction of rhizoxin with bovine brain tubulin." Cancer Res.50. 4277-4280 (1990)
[Publications] Y.Nagao: "Biomimetic,chemical,and spectroscopic evaluations for the radioーsencitizing potential of N1ーand N2ーsubstituted derivatives of 3ーnitroー1,2,4ーtriazole toward hypoxic cells in the radiotherapy." Tetrahedron. 46. 3211-3232 (1990)
[Publications] Y.Nagao: "Diastereoselective alkylation of chiral tin(II) enolates onto cyclic iminium ions.Asymmetric total synthesis of (ー)spinidine." Tetrahedron. 46. 6361-6380 (1990)
[Publications] T.Tsuruo: "A benzophenazine derivative,Nーβーdimethylaminoethyl 9ーcarboxyー5ーhydroxyー10ーmethoxyーbenzo[a]phenazineー6ーcarboxamide,as a new antitumor agent against multidrugーresistant and sensitive tumors." Cancer Chemother Pharmacol.26. 83-87 (1990)
[Publications] M.Watanabe: "Cellular pharmacology of MX2,a new morpholino anthracycline,in human pleiotropic drugーresistant cells." Cancer Res.51. 157-161 (1991)
[Publications] T.Sonoda: "Actiketal,a new member of the glutarimide antibiotics." J.Antibiotic. 44. 160-163 (1991)
[Publications] H.Osada: "Reveromycin A,a new antibiotic which inhibits the mitogenic activity of epidermal growth factor." J.Antibiotics. 44. 259-261 (1991)
[Publications] T.Ishibashi: "Presence of human papillomavirus typeー6ーrelated sequences in inverted nasal papillomas." Eur.Arch.Otorhinolaryngol.247. 296-299 (1990)

1990 Fiscal Year Annual Research Report

天然物由来制癌物質の探索とその化学的誘導に関する研究

Principal Investigator

瀬戸治男東京大学, 応用微生物研究所, 教授 (10013335)

Research Products

[Publications] T.Kawano: "Isolation and structures of new chromomycin antibiotics 02ー3D and 02ー3G from <Sreptomyce>_ーs <avellaneus>_ー." J.Antibiotics. 43. 110-113 (1990)

[Publications] M.Nakagawa: "A new depsipeptide antibiotic,variapeptin." Agric.Biol.Chem.54. 791-794 (1990)

[Publications] Y.Hayakawa: "A new depsipeptide antibiotic,citropeptin." Agric.Biol.Chem.54. 1007-1011 (1990)

[Publications] M.Nakagawa: "Structural studies on new depsipeptide antibiotics,variapeptin and citropeptin." J.Antibiotics. 43. 477-484 (1990)

[Publications] K.Shinーya: "The structure of benthocyanin A.A new free radical scavenger of microbial origin." Tetrahedron Lett.32. 943-946 (1990)

[Publications] K.Kakinuma: "Intramolecular stacking of gilvocarcin V:Tetraacetate as evidenced by NMR studies." J.Antibiot.43. 1077-1081 (1990)

[Publications] M.Yoshida: "Potent and specific inhibition of mammalian histone deacetylase both <in>_ー <vivo>_ー and <in>_ー <vitro>_ー by trichostatin A." J.Biol.Chem.265. 17174-17179 (1990)

[Publications] K.Abe: "Highly synchronous culture of fibroblasts from G2 block caused by staurosporine,a potent inhibitor of protein kinases." Exper.Cell Research. 192. 122-127 (1991)

[Publications] Y.Kato: "Studies on macrocyclic lactone antibiotics XIII.Antiーtubulin activity and cytotoxicity of rhizoxin derivatives:Synthesis of a photoaffinity derivative." J.Antibiotics. 44. 66-75 (1991)

[Publications] A.S.Sullivan: "Interaction of rhizoxin with bovine brain tubulin." Cancer Res.50. 4277-4280 (1990)

[Publications] Y.Nagao: "Biomimetic,chemical,and spectroscopic evaluations for the radioーsencitizing potential of N1ーand N2ーsubstituted derivatives of 3ーnitroー1,2,4ーtriazole toward hypoxic cells in the radiotherapy." Tetrahedron. 46. 3211-3232 (1990)

[Publications] Y.Nagao: "Diastereoselective alkylation of chiral tin(II) enolates onto cyclic iminium ions.Asymmetric total synthesis of (ー)spinidine." Tetrahedron. 46. 6361-6380 (1990)

[Publications] T.Tsuruo: "A benzophenazine derivative,Nーβーdimethylaminoethyl 9ーcarboxyー5ーhydroxyー10ーmethoxyーbenzo[a]phenazineー6ーcarboxamide,as a new antitumor agent against multidrugーresistant and sensitive tumors." Cancer Chemother Pharmacol.26. 83-87 (1990)

[Publications] M.Watanabe: "Cellular pharmacology of MX2,a new morpholino anthracycline,in human pleiotropic drugーresistant cells." Cancer Res.51. 157-161 (1991)

[Publications] T.Sonoda: "Actiketal,a new member of the glutarimide antibiotics." J.Antibiotic. 44. 160-163 (1991)

[Publications] H.Osada: "Reveromycin A,a new antibiotic which inhibits the mitogenic activity of epidermal growth factor." J.Antibiotics. 44. 259-261 (1991)

[Publications] T.Ishibashi: "Presence of human papillomavirus typeー6ーrelated sequences in inverted nasal papillomas." Eur.Arch.Otorhinolaryngol.247. 296-299 (1990)

1990 Fiscal Year Annual Research Report

天然物由来制癌物質の探索とその化学的誘導に関する研究

Principal Investigator

瀬戸 治男 東京大学, 応用微生物研究所, 教授 (10013335)

Research Products

[Publications] T.Kawano: "Isolation and structures of new chromomycin antibiotics 02ー3D and 02ー3G from <Sreptomyce>___ーs <avellaneus>___ー." J.Antibiotics. 43. 110-113 (1990)

[Publications] M.Nakagawa: "A new depsipeptide antibiotic,variapeptin." Agric.Biol.Chem.54. 791-794 (1990)

[Publications] Y.Hayakawa: "A new depsipeptide antibiotic,citropeptin." Agric.Biol.Chem.54. 1007-1011 (1990)

[Publications] M.Nakagawa: "Structural studies on new depsipeptide antibiotics,variapeptin and citropeptin." J.Antibiotics. 43. 477-484 (1990)

[Publications] K.Shinーya: "The structure of benthocyanin A.A new free radical scavenger of microbial origin." Tetrahedron Lett.32. 943-946 (1990)

[Publications] K.Kakinuma: "Intramolecular stacking of gilvocarcin V:Tetraacetate as evidenced by NMR studies." J.Antibiot.43. 1077-1081 (1990)

[Publications] M.Yoshida: "Potent and specific inhibition of mammalian histone deacetylase both <in>___ー <vivo>___ー and <in>___ー <vitro>___ー by trichostatin A." J.Biol.Chem.265. 17174-17179 (1990)

[Publications] K.Abe: "Highly synchronous culture of fibroblasts from G2 block caused by staurosporine,a potent inhibitor of protein kinases." Exper.Cell Research. 192. 122-127 (1991)

[Publications] Y.Kato: "Studies on macrocyclic lactone antibiotics XIII.Antiーtubulin activity and cytotoxicity of rhizoxin derivatives:Synthesis of a photoaffinity derivative." J.Antibiotics. 44. 66-75 (1991)

[Publications] A.S.Sullivan: "Interaction of rhizoxin with bovine brain tubulin." Cancer Res.50. 4277-4280 (1990)

[Publications] Y.Nagao: "Biomimetic,chemical,and spectroscopic evaluations for the radioーsencitizing potential of N1ーand N2ーsubstituted derivatives of 3ーnitroー1,2,4ーtriazole toward hypoxic cells in the radiotherapy." Tetrahedron. 46. 3211-3232 (1990)

[Publications] Y.Nagao: "Diastereoselective alkylation of chiral tin(II) enolates onto cyclic iminium ions.Asymmetric total synthesis of (ー)spinidine." Tetrahedron. 46. 6361-6380 (1990)

[Publications] T.Tsuruo: "A benzophenazine derivative,Nーβーdimethylaminoethyl 9ーcarboxyー5ーhydroxyー10ーmethoxyーbenzo[a]phenazineー6ーcarboxamide,as a new antitumor agent against multidrugーresistant and sensitive tumors." Cancer Chemother Pharmacol.26. 83-87 (1990)

[Publications] M.Watanabe: "Cellular pharmacology of MX2,a new morpholino anthracycline,in human pleiotropic drugーresistant cells." Cancer Res.51. 157-161 (1991)

[Publications] T.Sonoda: "Actiketal,a new member of the glutarimide antibiotics." J.Antibiotic. 44. 160-163 (1991)

[Publications] H.Osada: "Reveromycin A,a new antibiotic which inhibits the mitogenic activity of epidermal growth factor." J.Antibiotics. 44. 259-261 (1991)

[Publications] T.Ishibashi: "Presence of human papillomavirus typeー6ーrelated sequences in inverted nasal papillomas." Eur.Arch.Otorhinolaryngol.247. 296-299 (1990)

瀬戸治男東京大学, 応用微生物研究所, 教授 (10013335)

[Publications] T.Kawano: "Isolation and structures of new chromomycin antibiotics 02ー3D and 02ー3G from <Sreptomyce>_ーs <avellaneus>_ー." J.Antibiotics. 43. 110-113 (1990)

[Publications] M.Yoshida: "Potent and specific inhibition of mammalian histone deacetylase both <in>_ー <vivo>_ー and <in>_ー <vitro>_ー by trichostatin A." J.Biol.Chem.265. 17174-17179 (1990)