1999 Fiscal Year Annual Research Report

免疫賦活を目的としたα-N-アセチルガラクトサミニダーゼ阻害剤の制がん剤分子設計

Research Project

Project/Area Number	10672090
Research Institution	The University of Tokushima
Principal Investigator	堀均徳島大学, 工学部, 教授 (90119008)
Co-Investigator(Kenkyū-buntansha)	紺世秀子 (永沢秀子) 徳島大学, 工学部, 講師 (90207994)
Keywords	α-N-アセチルガラクトサミニダーゼ / 酵素阻害剤 / 免疫賦活剤 / 分子設計 / 制がん剤
Research Abstract	がん患者の免疫抑制の機構として,血中に増加するα-N-アセチルガラクトサミニダーゼ(α-NaGalase)によってマクロファージ活性化因子(GcMAF)前駆体が分解することが提唱されている.(Yamamoto,N.et al.,1998)このような機構を検証するため,種々のがん細胞におけるα-NaGalase酵素活性について解析を行った.さらにがん患者の免疫賦活を目的として,α-NaGalase阻害剤設計を検討した. 1)がん細胞としてHCT116,HepG2細胞と正常細胞としてChung Liver細胞及びラットhepatocytesを用いて,α-NaGalase活性を測定したところ,がん細胞において活性が有意に上昇していた.この際,がん細胞中のα-NaGalaseが,endo型であるか,exo型であるかについてそれぞれのPNP基質を用いて調べたところ,endo型活性は認められなかった.ガン患者血清中のα-NaGalaseに関しても同様に検討したところ,endo活性は認められなかった.これより,GcMAF前駆体であるGcProteinのα-NaGalaseによる糖鎖分解の機構(endo型切断)について再検討を要することがあきらかになった.一方,血清より精製したGcProteinからin situで得られたGcMAFによるマクロファージのO^2_-産生能の上昇が認められた. 2)mannosidaze阻害剤でアザ糖であるスワンソニンに免疫賦活作用があることから,これをリード化合物として,その水酸基の2面角をコントロールして阻害するグリコシダーゼの種類を制御することを目的にsp2炭素の導入に基づく分子設計を行い,合成ルートの確立を検討した.その結果エナミン誘導体の合成に成功した.これらについてα-NaGalaseを含む各種グリコシダーゼ阻害活性について現在検討中である.

Research Products

(12 results)

All Other

All Publications (12 results)

[Publications] Zhu,J-W,H Nagasawa,H Hori et al.: "Elucidation of Strict Structural Requirements of Brefeldin A as an Inducer of Differentination and Apoptosis."Bioorg.Med.Chem.. 8. 455-463 (2000)
[Publications] Nagasawa,H.,H.Hori et al.: "Apoptosis induction in HCT116 cells by cytochalasins isolated from the fungus Daldinia vernicosa."Phytomedicine. 6. 403-409 (2000)
[Publications] A-Z,Medhat,H Hori et.al.: "Studies of methyl2-nitroimidazole-1-acetohydroxamate(KIN-804)1.Effect on free radical scavenging system in mice bearing Ehrlich ascites carcinoma"Biol.Pharm.Bull.. 23(2). 190-194 (2000)
[Publications] A-Z,Medhat,H Hori et.al.: "Studies of methyl2-nitroimidazole-2-acetohydroxamate(KIN-804)1.Effect on certain antioxidant enzyme system in mice bearing Ehrlich ascites carcinoma"Biol.Pharm.Bull.. 23(2). 195-198 (2000)
[Publications] Inomata,T,H Nagasawa,H Hori et al.: "The immunopotentiation Effects of the Bifunctional Radiosensitizer KIN-806 in comparison with its Analogs KIN-804 and KIN-844."Oncology Reports. 6(6). 1209-1212 (1999)
[Publications] Masunaga,S,K Ono,H Hori et al.: "Modification of tirapazamine-induced cytotoxicity in combination with mild hyperthermina:reference to effect on quiescent tumor cells."Int.J.Hyperthermia.. 15(1). 7-16 (1999)
[Publications] T.Inomata,S.Yoshida,H,Nagasawa,H.Hori et al.: "The immunopotentiation Effects of the Bifunctional Radiosensitizer KIN-806 in comparison with its Analogs KIN-804Å@ and KIN-844."Oncology Reports. 6. 1209-1212 (1999)
[Publications] I.Shimizu,Y.Mizobuchi,F.Liu,T.Miura,H.Hori et al.: "Effects of sho-saiko-to,a japanese herbal medicine,on hepatic fibrosis in rats"Hepatalogy. 29. 49-60 (1999)
[Publications] H.Hori,M.Ishibashi,H.Nagasawa,Y.Uto,et al.: "Enhancement effect of methyl a-D-glucoside for inhibitory effects of antioxidants on ADP/Fe2+-induced lipid perox idation in rat liver mitochondria"Adv.Exp.Med.Biol.(Oxygen Transport to Tissue XXI). XXI. 395-402 (1999)
[Publications] T.Inomata,S.Kariya,H.Nagasawa,H.Hori,et al.: "The Effects of the Lung Metastasis Suppression of the Bifunctional New Radiosensitizer KIN-806"Int.J.Mol.Med.. 4. 257-260 (1999)
[Publications] S.Masunaga,H.Hori,H.Nagasawa,Y.Uto et al.: "Potentially lethal damage repair by total and quiscent tumor cells following various DNA-damaging treatments"Radiation Medicine. 17. 259-264 (1999)
[Publications] K.Ohkura,H.Hori: "Analysis of structure-permeability of correlation of nitrophenol analogues in newborn at abdominal skin using semiempirical molecular orbital calculation"Bioorg.Med.Chem.. 7. 309-314 (1999)

1999 Fiscal Year Annual Research Report

免疫賦活を目的としたα-N-アセチルガラクトサミニダーゼ阻害剤の制がん剤分子設計

Principal Investigator

堀 均 徳島大学, 工学部, 教授 (90119008)

Research Products

[Publications] Zhu,J-W,H Nagasawa,H Hori et al.: "Elucidation of Strict Structural Requirements of Brefeldin A as an Inducer of Differentination and Apoptosis."Bioorg.Med.Chem.. 8. 455-463 (2000)

[Publications] Nagasawa,H.,H.Hori et al.: "Apoptosis induction in HCT116 cells by cytochalasins isolated from the fungus Daldinia vernicosa."Phytomedicine. 6. 403-409 (2000)

[Publications] A-Z,Medhat,H Hori et.al.: "Studies of methyl2-nitroimidazole-1-acetohydroxamate(KIN-804)1.Effect on free radical scavenging system in mice bearing Ehrlich ascites carcinoma"Biol.Pharm.Bull.. 23(2). 190-194 (2000)

[Publications] A-Z,Medhat,H Hori et.al.: "Studies of methyl2-nitroimidazole-2-acetohydroxamate(KIN-804)1.Effect on certain antioxidant enzyme system in mice bearing Ehrlich ascites carcinoma"Biol.Pharm.Bull.. 23(2). 195-198 (2000)

[Publications] Inomata,T,H Nagasawa,H Hori et al.: "The immunopotentiation Effects of the Bifunctional Radiosensitizer KIN-806 in comparison with its Analogs KIN-804 and KIN-844."Oncology Reports. 6(6). 1209-1212 (1999)

[Publications] Masunaga,S,K Ono,H Hori et al.: "Modification of tirapazamine-induced cytotoxicity in combination with mild hyperthermina:reference to effect on quiescent tumor cells."Int.J.Hyperthermia.. 15(1). 7-16 (1999)

[Publications] T.Inomata,S.Yoshida,H,Nagasawa,H.Hori et al.: "The immunopotentiation Effects of the Bifunctional Radiosensitizer KIN-806 in comparison with its Analogs KIN-804Å@ and KIN-844."Oncology Reports. 6. 1209-1212 (1999)

[Publications] I.Shimizu,Y.Mizobuchi,F.Liu,T.Miura,H.Hori et al.: "Effects of sho-saiko-to,a japanese herbal medicine,on hepatic fibrosis in rats"Hepatalogy. 29. 49-60 (1999)

[Publications] H.Hori,M.Ishibashi,H.Nagasawa,Y.Uto,et al.: "Enhancement effect of methyl a-D-glucoside for inhibitory effects of antioxidants on ADP/Fe2+-induced lipid perox idation in rat liver mitochondria"Adv.Exp.Med.Biol.(Oxygen Transport to Tissue XXI). XXI. 395-402 (1999)

[Publications] T.Inomata,S.Kariya,H.Nagasawa,H.Hori,et al.: "The Effects of the Lung Metastasis Suppression of the Bifunctional New Radiosensitizer KIN-806"Int.J.Mol.Med.. 4. 257-260 (1999)

[Publications] S.Masunaga,H.Hori,H.Nagasawa,Y.Uto et al.: "Potentially lethal damage repair by total and quiscent tumor cells following various DNA-damaging treatments"Radiation Medicine. 17. 259-264 (1999)

[Publications] K.Ohkura,H.Hori: "Analysis of structure-permeability of correlation of nitrophenol analogues in newborn at abdominal skin using semiempirical molecular orbital calculation"Bioorg.Med.Chem.. 7. 309-314 (1999)

堀均徳島大学, 工学部, 教授 (90119008)