1989 Fiscal Year Annual Research Report

休止期細胞の動員と転移抑制効果を有する新合成制癌剤の探索

Research Project

Project/Area Number	01010024
Research Institution	Kanazawa University
Principal Investigator	佐々木琢磨金沢大学, がん研究所, 教授 (90109976)
Co-Investigator(Kenkyū-buntansha)	大場義樹金沢大学, 薬学部, 教授 (10012634) 米田文郎京都大学, 薬学部, 教授 (80040327) 川添豊名古屋市立大学, 薬学部, 教授 (80106252) 兼松顕九州大学, 薬学部, 教授 (70023041) 上田亨北海道大学, 薬学部, 教授 (00001032)
Keywords	5ーフルオロー2'ーメチリデンシチジン / エチルイミダゾールリボシド / 蛋白リン酸化酵素 / Aーキナーゼ / Cーキナーゼ / シクロヘキサンジアミン白金錯体 / 5ーデアザフラビン類 / シコニン類
Research Abstract	我々が既に報告した2'-メチリデンシチジン(DMDC)は臨床応用の可能性が極めて高い特色ある抗癌剤として開発中であるが、このDMDCの2'ーメチリデンヌクレオシド誘導体である5ーフルオロシトシン体(5FDMDC)は、AraC及び5FUなどの既存抗癌剤が無効なヌードマウスに移植したヒト腫癌に対しても有効であることが確認された。さらに、各種ヒト腫癌細胞に対するin vitroのターゲットスペクトラムも明らかにAraC、5FUとは異なり、AraCの不活性化酵素であるシチジンデアミナーゼによって不活性化されず、骨髄毒性もAraCに比して弱いという特徴を有することも明らかなった。一方、核酸塩基部に不飽和官能基を有するヌクレオシドとして新たにエチルイミダゾールリボシド(EIR)を合成し、その抗腫癌活性を検討結果、in vivoの実験系で固型腫瘍に対しても有効であり、且つ低毒性の物質であることが確認された。Cyclic AMP 依存性蛋白リン酸化酵素Aー及びCーキナーゼに対する一連のイソキノリン及びスタウロスポリン誘導体の作用と細胞増殖に及ぼす影響を検討結果、Nー[2ー(4ーchloro-alpha-methylcinnamylamino)ethyl]-5-isoquinolinesulfonamide(H-87)がAーキナーゼを強く阻害し、AーキナーゼがG_1→S期の移行を促進的に、S→G_2期の移行には抑制的に関与していることが示唆された。胆汁酸を脱離基とするシクロヘキサンジアミン白金錯体類を新たに合成し検討結果、癌細胞の肺転移を顕著に抑制することが明らかとなった。全く新しいタイプの合成抗癌剤としての進展が期待される電子伝達系の5ーデアザフラビン類及び関連化合物の活性構造相関をin vitroの抗腫瘍活性を基にほぼ確立し、同じく新合野であるシコニン類縁体の合成に関しても簡便で信頼性のある合成法の確立に成功し、それらの抗腫癌性、癌転移抑制効果及び癌細胞周期に与える効果を検討中である。

Research Products
(22 results)

All Other

All Publications (22 results)

[Publications] K.Yamagami: "Antitumor activity of 2'-deoxy-2'-methylidenecytidine,a new 2'-deoxy-cytidine derivative" Cancer Res.49. (1990)
[Publications] T.Sasaki: "Antitumor antibiotics" J.Pr.Ph.40. 751-757 (1989)
[Publications] S.kanatomo: "Sparsomycin Analogs.VI.Synthesis and antitumor activity of octylsparsomyin analogs" Chem.Pharm.Bull.37. 688-691 (1989)
[Publications] K.Tomita: "DNA repair and drug resistance:Enhancement of the effects of anticancer agents by DNA repair inhibitors" Jpn.J.Cancer & Chemotherapy. 16. 576-584 (1989)
[Publications] M.Sugihara: "High-dose metgotrexate therapy with leucovorin rescue on human osteosarcoma by use of embryonated chick assay" Cent.Jpn.J.Orthop.Traumat.32. 410-412 (1989)
[Publications] K.Miyamoto: "Stimulatory and inhibitory effects of forskolin on adenylate cyclase in rat normal hepatocytes and hepatoma cells" J.Pharmacobio-Dyn.12. 87-93 (1989)
[Publications] K.Miyamoto: "Forskolin inhibits the Gs-stimulated adenylate cyclase in rat ascites hepatoma AH66F cells" Exp.Cell.Res.184. 219-227 (1989)
[Publications] K.Miyamoto: "Circumvention of multidrug resistance in P388 murine leukemia cells by a novel inhibitor of cyclic AMP-dependent protein kinase,H-87" Cncer Letters. (1990)
[Publications] F.Sanae: "Altered specificity of adrenergic receptors and catechol-amine-response of rat ascites hepatoma AH130" Cancer Res.49. 6242-6246 (1989)
[Publications] I.Fujii: "Flexicibly crown enther-capped beta-cyclodextrin" Bioorg.Chem.17. 240-244 (1989)
[Publications] K.Kanematsu: "An efficient synthesis of a key intermediate of Forskolin" J.Chem.Soc.1989. 1028-1029 (1989)
[Publications] Y.Yamaguchi: "Chirality transfer from the furan ring transfer reaction" J.Chem.Soc.1989. 470-472 (1989)
[Publications] M.Aso: "Successive Michael Reaction-sigmatropic rearrangement of plyquinones with silyl ketene acetals" J.Org.Chem.54. 5597-5603 (1989)
[Publications] K.Kohda: "Deoxyribonucleic acid(DNA)damage induced by bleomycin-Fe(II)in vitro:Formation of 8-hydroxyguanine residue in DNA" Chem.Pharm.Bull.37. 1028-1030 (1989)
[Publications] T.Suzuki: "Enhanced cytotoxicity in stimultaneous and sequencial drug-heat treatments to cultured Chinese hamster V79 cells" Chem.Pharm.Bull.37. 3058-3060 (1989)
[Publications] K.Fukuchi: "Inhibition of Herpes simplex virus infection by pine cone antitumor substances" Anticancer Res.9. 313-318 (1989)
[Publications] K.Kohda: "Ulicyclamide is cytotoxic against L1210 cells in vitro and inhibits both DNA and RNA synthese" Biochem.Pharmacol.38. 4500-4502 (1989)
[Publications] T.Akiyama: "The reductive repair of 1,3-dimethylthymine bromohydrin into 1,3-dimethythymine by 1,5-dihydro-5-deazaglavin or 1,4-dihydroquinoline" J.Heterocyclic Chem.26. 877-878 (1989)
[Publications] R.Herayama: "The autorecyclimg oxidation of bezylamine by synthetic 8-hydroxy-5-deazaflavin derivatives" J.Heterocyclic Chem.26. 1255-1259 (1989)
[Publications] T.Kawamoto: "Synthesis and reaction of a new type of 5-deazaflavin with axial and planar chirality" Tetrahedron Letters. 30. 7431-7434 (1989)
[Publications] F.Yoneda: "Synthesis of bis(pyridodipyrimidines)as autorecycling redox catalysts and their remarkable turnover in the oxidation of alchols" J.Am.Chem.Soc.111. 9199-9202 (1989)
[Publications] M.Toyota: "A novel synthesis of basic carbon framework of Fredericamycin A.Promising routes for the spiro chiral center construction of C,D-ring system" Tetrahedron Letters. 30. 829-833 (1989)

1989 Fiscal Year Annual Research Report

休止期細胞の動員と転移抑制効果を有する新合成制癌剤の探索

Principal Investigator

佐々木 琢磨 金沢大学, がん研究所, 教授 (90109976)

Research Products

[Publications] K.Yamagami: "Antitumor activity of 2'-deoxy-2'-methylidenecytidine,a new 2'-deoxy-cytidine derivative" Cancer Res.49. (1990)

[Publications] T.Sasaki: "Antitumor antibiotics" J.Pr.Ph.40. 751-757 (1989)

[Publications] S.kanatomo: "Sparsomycin Analogs.VI.Synthesis and antitumor activity of octylsparsomyin analogs" Chem.Pharm.Bull.37. 688-691 (1989)

[Publications] K.Tomita: "DNA repair and drug resistance:Enhancement of the effects of anticancer agents by DNA repair inhibitors" Jpn.J.Cancer & Chemotherapy. 16. 576-584 (1989)

[Publications] M.Sugihara: "High-dose metgotrexate therapy with leucovorin rescue on human osteosarcoma by use of embryonated chick assay" Cent.Jpn.J.Orthop.Traumat.32. 410-412 (1989)

[Publications] K.Miyamoto: "Stimulatory and inhibitory effects of forskolin on adenylate cyclase in rat normal hepatocytes and hepatoma cells" J.Pharmacobio-Dyn.12. 87-93 (1989)

[Publications] K.Miyamoto: "Forskolin inhibits the Gs-stimulated adenylate cyclase in rat ascites hepatoma AH66F cells" Exp.Cell.Res.184. 219-227 (1989)

[Publications] K.Miyamoto: "Circumvention of multidrug resistance in P388 murine leukemia cells by a novel inhibitor of cyclic AMP-dependent protein kinase,H-87" Cncer Letters. (1990)

[Publications] F.Sanae: "Altered specificity of adrenergic receptors and catechol-amine-response of rat ascites hepatoma AH130" Cancer Res.49. 6242-6246 (1989)

[Publications] I.Fujii: "Flexicibly crown enther-capped beta-cyclodextrin" Bioorg.Chem.17. 240-244 (1989)

[Publications] K.Kanematsu: "An efficient synthesis of a key intermediate of Forskolin" J.Chem.Soc.1989. 1028-1029 (1989)

[Publications] Y.Yamaguchi: "Chirality transfer from the furan ring transfer reaction" J.Chem.Soc.1989. 470-472 (1989)

[Publications] M.Aso: "Successive Michael Reaction-sigmatropic rearrangement of plyquinones with silyl ketene acetals" J.Org.Chem.54. 5597-5603 (1989)

[Publications] K.Kohda: "Deoxyribonucleic acid(DNA)damage induced by bleomycin-Fe(II)in vitro:Formation of 8-hydroxyguanine residue in DNA" Chem.Pharm.Bull.37. 1028-1030 (1989)

[Publications] T.Suzuki: "Enhanced cytotoxicity in stimultaneous and sequencial drug-heat treatments to cultured Chinese hamster V79 cells" Chem.Pharm.Bull.37. 3058-3060 (1989)

[Publications] K.Fukuchi: "Inhibition of Herpes simplex virus infection by pine cone antitumor substances" Anticancer Res.9. 313-318 (1989)

[Publications] K.Kohda: "Ulicyclamide is cytotoxic against L1210 cells in vitro and inhibits both DNA and RNA synthese" Biochem.Pharmacol.38. 4500-4502 (1989)

[Publications] T.Akiyama: "The reductive repair of 1,3-dimethylthymine bromohydrin into 1,3-dimethythymine by 1,5-dihydro-5-deazaglavin or 1,4-dihydroquinoline" J.Heterocyclic Chem.26. 877-878 (1989)

[Publications] R.Herayama: "The autorecyclimg oxidation of bezylamine by synthetic 8-hydroxy-5-deazaflavin derivatives" J.Heterocyclic Chem.26. 1255-1259 (1989)

[Publications] T.Kawamoto: "Synthesis and reaction of a new type of 5-deazaflavin with axial and planar chirality" Tetrahedron Letters. 30. 7431-7434 (1989)

[Publications] F.Yoneda: "Synthesis of bis(pyridodipyrimidines)as autorecycling redox catalysts and their remarkable turnover in the oxidation of alchols" J.Am.Chem.Soc.111. 9199-9202 (1989)

[Publications] M.Toyota: "A novel synthesis of basic carbon framework of Fredericamycin A.Promising routes for the spiro chiral center construction of C,D-ring system" Tetrahedron Letters. 30. 829-833 (1989)

佐々木琢磨金沢大学, がん研究所, 教授 (90109976)