JP6944690B2 - グルタチオン−s−トランスフェラーゼ(gst)の発現増強剤 - Google Patents
グルタチオン−s−トランスフェラーゼ(gst)の発現増強剤 Download PDFInfo
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- JP6944690B2 JP6944690B2 JP2017029992A JP2017029992A JP6944690B2 JP 6944690 B2 JP6944690 B2 JP 6944690B2 JP 2017029992 A JP2017029992 A JP 2017029992A JP 2017029992 A JP2017029992 A JP 2017029992A JP 6944690 B2 JP6944690 B2 JP 6944690B2
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- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
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- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 1
- 229960002695 phenobarbital Drugs 0.000 description 1
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- MQIHULHVANZSER-XPQLPGEHSA-N phenyl (2e,4e)-hexa-2,4-dienoate Chemical compound C\C=C\C=C\C(=O)OC1=CC=CC=C1 MQIHULHVANZSER-XPQLPGEHSA-N 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 description 1
- 238000006552 photochemical reaction Methods 0.000 description 1
- 230000002165 photosensitisation Effects 0.000 description 1
- ZWLUXSQADUDCSB-UHFFFAOYSA-N phthalaldehyde Chemical compound O=CC1=CC=CC=C1C=O ZWLUXSQADUDCSB-UHFFFAOYSA-N 0.000 description 1
- SHUZOJHMOBOZST-UHFFFAOYSA-N phylloquinone Natural products CC(C)CCCCC(C)CCC(C)CCCC(=CCC1=C(C)C(=O)c2ccccc2C1=O)C SHUZOJHMOBOZST-UHFFFAOYSA-N 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 235000021110 pickles Nutrition 0.000 description 1
- 235000015108 pies Nutrition 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 108010089000 polyamine oxidase Proteins 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 235000013324 preserved food Nutrition 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- XCRPPAPDRUBKRJ-UHFFFAOYSA-N quinolin-7-ol Chemical compound C1=CC=NC2=CC(O)=CC=C21 XCRPPAPDRUBKRJ-UHFFFAOYSA-N 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 235000013580 sausages Nutrition 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 125000005624 silicic acid group Chemical class 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000011888 snacks Nutrition 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229940023144 sodium glycolate Drugs 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 235000014214 soft drink Nutrition 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 235000014347 soups Nutrition 0.000 description 1
- 235000013322 soy milk Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 229940063673 spermidine Drugs 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 235000013547 stew Nutrition 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 210000004304 subcutaneous tissue Anatomy 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 235000013616 tea Nutrition 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- 210000000966 temporal muscle Anatomy 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical group C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 230000001732 thrombotic effect Effects 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- AOBORMOPSGHCAX-DGHZZKTQSA-N tocofersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-DGHZZKTQSA-N 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000011573 trace mineral Substances 0.000 description 1
- 235000013619 trace mineral Nutrition 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- JEJAMASKDTUEBZ-UHFFFAOYSA-N tris(1,1,3-tribromo-2,2-dimethylpropyl) phosphate Chemical compound BrCC(C)(C)C(Br)(Br)OP(=O)(OC(Br)(Br)C(C)(C)CBr)OC(Br)(Br)C(C)(C)CBr JEJAMASKDTUEBZ-UHFFFAOYSA-N 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 235000019168 vitamin K Nutrition 0.000 description 1
- 239000011712 vitamin K Substances 0.000 description 1
- 150000003721 vitamin K derivatives Chemical class 0.000 description 1
- 229940046010 vitamin k Drugs 0.000 description 1
- 230000002087 whitening effect Effects 0.000 description 1
- 229910052724 xenon Inorganic materials 0.000 description 1
- FHNFHKCVQCLJFQ-UHFFFAOYSA-N xenon atom Chemical compound [Xe] FHNFHKCVQCLJFQ-UHFFFAOYSA-N 0.000 description 1
- 235000013618 yogurt Nutrition 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- 235000014692 zinc oxide Nutrition 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
Images
Landscapes
- Coloring Foods And Improving Nutritive Qualities (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
で表される化合物の少なくとも1種を有効成分として含有する、脳血管障害および/または認知症の予防、治療および/または症状進展抑制剤が提供される。
以下に示す実験により得られた全てのデータは平均値±標準誤差の値として示した。また、治療効果の評価では、分散分析を行った後、多重比較検定についてはTukeyの検定により行った。また、予防効果の評価では、分散分析を行った後、多重比較検定についてはDunnettの検定により行った。なお、危険率5%以下の場合に統計的に有意差があるものとして*印を付した。同様に、危険率1%以下および0.1%以下の場合にはそれぞれ**印および***印を付した。また、統計処理ソフトとしてはGraph pad Prism 5を使用した
≪NACおよびそのエステル誘導体の準備とこれらを含む溶液の調製≫
NACおよびNACMeについては、Sigma社より購入したものを用いた。一方、NACEtおよびNACBnについては、以下の手法により合成したものを用いた。なお、すべての試薬および溶剤としては市販のものを用いた。
文献(Mechanistic proposal for the formation of specific immunogenic complexes via a radical pathway: a key step in allergic contact dermatitis to olefinic hydroperoxides. Johansson S., Redeby T., Altamore T.M., Nilsson U., Borje A., Chem. Res. Toxicol., 22, 1774−1781, (2009))に記載の手法を改変した手法により、N−アセチルシステインエチルエステル(NACEt)を合成した。
MS m/z:191(M)+。
ベンジルアルコール(2.0mL、19.3mmol)およびN,N’−ジイソプロピルカルボジイミド(3.0mL、19.5mmol)を、アルゴン雰囲気下、室温にて15時間、CuCl(42.0mg、0.42mmol)の存在下で撹拌した。粗生成物をAl2O3オープンカラムクロマトグラフィー(溶剤系は30%酢酸エチル/n−ヘキサン)により精製して、O−ベンジルN,N’−ジイソプロピルイソウレア(4.25g)を得た。
13C−NMR(CDCl3,100MHz) a:151.5,138.0,128.2,127.6,127.3,66.6,46.3,43.4,24.3,24.0。
本実施例において、全ての動物実験は千葉大学動物実験委員会による許可を受け、千葉大学動物実験実施規定に基づいて実施した。
上記で準備したNACおよびそのエステル誘導体3種(NACMe、NACEtおよびNACBn)の脳梗塞に対する治療効果について、上記で作製した脳梗塞モデルマウスを用い、以下の手法により検討した。
上記で準備したNACおよびそのエステル誘導体2種(NACEtおよびNACBn)の脳梗塞に対する予防効果について、上記で作製した脳梗塞モデルマウスを用い、以下の手法により検討した。
続いて、上述したNACエステル誘導体の予防投与によって梗塞体積が減少したメカニズムについて検討を行った。
まず、脳組織におけるポリアミン量の変化について検討した。ここでは、NACおよびそのエステル誘導体2種(NACEtおよびNACBn)のそれぞれを予防投与したマウスについて、脳梗塞を誘導してから24時間後に脳を摘出し、正常部位および梗塞部位のポリアミンを抽出してHPLCによって定量した。
続いて、アクロレインの毒性解除を担う生体内物質であるグルタチオン(GSH)量の脳組織における変化について検討した。ここで、グルタチオンには酸化型グルタチオンおよび還元型グルタチオンの2種類が存在するが、脳においては還元型グルタチオンの割合が99%を超えることから、両者をまとめて総グルタチオン(tGSH)として測定を行った。
続いて、脳組織におけるPC−Acro量の変化について検討した。上述したように、PC−Acroはタンパク質抱合アクロレインを意味し、この量の増加は、アクロレインのシステイン残基等への結合によってタンパク質が不活性化されている程度が大きいことを示唆する。
そこで本発明者らは、哺乳動物の脳において発現してアクロレインを基質とするGST種であるGST−π、GST−θおよびGST−μに着目し、脳組織におけるこれらの発現量を検討した。
なお、GST−πはアクロレインの基質特異性が高いことや、脳卒中患者において血中GST−π農度と脳卒中の開始時間に関係があることが報告されている。そこで本発明者らはGST−πに着目し、アクロレインのグルタチオン抱合に対するGST−πの影響について検討した。
Claims (4)
- 前記一般式(1)におけるRが、水素原子、置換もしくは非置換の炭素数1〜30のアルキル基、または置換もしくは非置換の炭素数7〜30のアリールアルキル基である、請求項1に記載の発現増強剤。
- 前記一般式(1)におけるRが、水素原子、炭素数1〜8のアルキル基、または炭素数7〜14のアリールアルキル基である、請求項2に記載の発現増強剤。
- 前記一般式(1)におけるRが、水素原子、メチル基、エチル基またはベンジル基である、請求項3に記載の発現増強剤。
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