ドラッグデザインによる新しい抗がん剤の合成

• Project/Area Number: 09255101
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas (A)
• Allocation Type: Single-year Grants
• Research Institution: Hokkaido University
• Principal Investigator: 松田 彰 北海道大学, 大学院・薬学研究科, 教授 (90157313)
• Co-Investigator(Kenkyū-buntansha): 綿矢 有佑 岡山大学, 大学院・薬学研究科, 教授 (90127598) ; 関根 光男 (関根 光雄) 東京工業大学, 大学院・生命理工学研究科, 教授 (40111679) ; 渋谷 雅之 徳島大学, 薬学部, 教授 (40027066) ; 佐々木 琢磨 金沢大学, がん研究所, 教授 (90109976)
• Project Period (FY): 1999
• Project Status: Completed (Fiscal Year 1999)
• Budget Amount: ¥75,000,000 (Direct Cost: ¥75,000,000); Fiscal Year 1999: ¥25,000,000 (Direct Cost: ¥25,000,000); Fiscal Year 1998: ¥25,000,000 (Direct Cost: ¥25,000,000); Fiscal Year 1997: ¥25,000,000 (Direct Cost: ¥25,000,000)
• Keywords: 代謝拮抗剤 / ヌクレオシド / 抗がん剤 / アポトーシス / カスパーゼ / p53 / RNA合成阻害剤 / ドラッグデザイン / 血管新生 / エンジイン

Research Abstract

1.新規抗腫瘍性ヌクレオシドEcydは、注射薬として固形癌を対象に米国で第1相臨床試験に入った.2.種々のヒト腫瘍細胞のエチニルヌクレオシドに対するin vitro薬剤感受性を調べ,各細胞におけるp53の表現型との関連性を検討し,変異型p53遺伝子を有する腫瘍細胞は,野生p53遺伝子を有する腫瘍細胞に比較し有意に感受性が低いことを明らかにした.3.EcydおよびEurdは哺乳動物細胞内でEcyd 5'-triphosphate(ECTP),またはethynyluridine 5'-triphosphate(EUTP)に代謝され,これらがCTPまたはUTPとRNA polymeraseを競合的に強く阻害した(ECTP ; Ki=21nM、CTP ; Km=8μM、EUTP ; Ki=84nM、CTP ; Km=13μM).ヒト癌細胞でのECTPの細胞内滞留時間の半減期は15〜30時間であった.EcydはFM3A細胞の28SrRNAのfragmentationを引き起こし、3.2kb,3.0kb,および1.5kbに断片化した.その切断様式を解明した.さらに,Ecydによる作用機序の一つに内因性Rnase Lの活性化経路が関与している可能性が示唆された.4.Ecydの構造―活性相関を調べる目的で,4'α-位に種々の炭素官能基を導入したdCydおよびCyd誘導体を合成した.これらの中で,4'α-Me,CN,およびC=CH体がL1210細胞に10^<-7>Mで増殖抑制活性を示したが,KB細胞には活性を示さなかった.しかし,こららの化合物は,強力な抗HIV作用を示した.5.蛋白合成阻害剤であるホスミドシンの脱メチル体とそのN-アセチル体を合成した.これらは,種々のヒト胃・大腸がん細胞の増殖をIC_<50>=6-190μMで抑制した.6.ハロゲン化オリゴピロール誘導体を合成し、それらのDNA切断活性と抗腫瘍活性を測定し活性物質を見いだした.

Research Products

• [Publications] Takatori S., et al.: "Antitumor mechanisms and metabolism of novel antitumor nucleoside analogues, 1-(3-C-ethynyl-β-D-ribo-pentofuranosyl)cytosine and 1-(3-C-ethynyl-β-D-ribo-pentofuranosyl)uracil"Cancer Chemother.Pharmacol.. 44. 97-104 (1999)
• [Publications] Hanaoka K., et al.: "Antitumor activity and novel DNA-self-strand-breaking mechanism of CNDAC(1-(2-C-cyano-2-deoxy-β-D-arabino-pentofuranosyl)cytosine and its N^4-palmitoyl derivative(CS-682)"Int.J.Cancer. 82. 226-236 (1999)
• [Publications] Minakawa N., et at.: "Mechanism-based design of inosine 5'-monophosphate dehydrogenase inhibitors : Synthesis and biological activities of 5-ethynyl-1-β-D-ribofuranosyl-imidazole-4-carboxamide(EICAR) and its drivatives"Current Med.Chem.. 6. 597-610 (1999)
• [Publications] Nomura M., et al.: "Synthesis and biological activities of 4'α-C-branched-chain sugar pyrimidine nucleosides"J.Med.Chem.. 42. 2901-2908 (1999)
• [Publications] Zhang M., et al.: "Determinants in chemosensitivity of oncogene-transformed NIH3T3 cells to 2'-C-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine"Internatl.J.Oncol.. 14. 543-549 (1999)
• [Publications] Wakayama M., et al.: "Decarboxylative cycloaromatization of enediyne model compounds-mechanism of radical and ionic pathway"Tetrahedron Lett.. 41. 95-98 (2000)
• [Publications] K.Nishikawa: "A prospective evaluation of new rapid urease tests before and after eradication treatment of Helicobacter pylori, in comparison with histology, culture and ^<13>C-urea brea breath test"Gastrointest. Endosc.. 51. 164-168 (2000)
• [Publications] Hattori,H.,et al.: "The structural requirements of the sugar moiety for the antitumor activities of new nucleoside antimetabolites, 1-(3-C-ethynyl-β-D-ribo-pentofuranosyl) cytosine and -uracil." J.Med.Chem.41. 2892-2902 (1998)
• [Publications] Ogawa,A.,et al.: "Synthesis and antituor activity of nucleosides that have a hydroxylamino group instead of a hydroxyl group at the 2'or 3'position at the sugar moiety." J.Med.Chem.41. 5094-5107 (1998)
• [Publications] Ogawa,A.,et al.: "2'-Deoxy-2'-hydroxylaminocytidine : A new antitumor nucleoside that inhibits DNA synthesis although it has a ribonucleoside structure." Bioorg.Med.Chem.lett.8. 1913-1918 (1998)
• [Publications] Miura,S.,et al.: "Antitumor activity of a-novel orally effective nucleoside, 1-(2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine." Cacer Lett.129. 103-110 (1998)
• [Publications] Minakawa,N.,et al.: "Ring-expanded purine nucleosides. The synthesis and cytotoxicity of imidazo[4,5-c]azepine nucleosides." Tetrahedron. 54. 13517-13528 (1998)
• [Publications] Takatori.S.,et al.: "The characterization of cell death induced by 1-(3-C-ethynyl-β-D-ribo-pentofuranosyl) cytosine (ECyd) in FM3A cells." Nucleosides Nucleotides.17. 1309-1317 (1998)
• [Publications] Ichikawa,S.et al.: "Synthesis of 3′-β-branched uridine derivatines via intramolecular Raformatsky-type reaction promoted by SmI_2." J.Org.Chem.62. 1368-1375 (1997)
• [Publications] Hassam,A.E.A.et al.: "Chelation-controlled and nonchilation controlled diasterestacial selective thiophenol addition reactions at the 2′-position...." J.Org.Chem.62. 11-17 (1997)
• [Publications] Nakanishi,T.et al.: "Carrier-mediated transport of oligopeptides on human fibrosarcoma cell line HT-1080" Cancer Res.57. 4118-4112 (1997)
• [Publications] Ohta,Y.et al.: "Vascular endtherial growth factorand lymphonode metastasis in primary lung cancer." Br.J.Cancer. 76. 1041-1045 (1997)
• [Publications] Wada,T.et al.: "Chemical synthesis of oligodeoxyribonuclestides using N-unprotected H-phosphonate monomers....." J.Am.Chem.Soc.119. 12710-12721 (1997)
• [Publications] Shishido,K.et al.: "Synthesis and evaluation of the hybid molecules possessing DNA-cleaving activity." Bioorg.Med.Chem.Lett.7. 2617-2622 (1997)