JP6721583B2 - 3−ヒドロキシブチラートのオリゴマー体 - Google Patents
3−ヒドロキシブチラートのオリゴマー体 Download PDFInfo
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- JP6721583B2 JP6721583B2 JP2017524113A JP2017524113A JP6721583B2 JP 6721583 B2 JP6721583 B2 JP 6721583B2 JP 2017524113 A JP2017524113 A JP 2017524113A JP 2017524113 A JP2017524113 A JP 2017524113A JP 6721583 B2 JP6721583 B2 JP 6721583B2
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Description
Zはカルボン酸およびその医薬的に許容される塩またはエステルから選ばれ、
nは1または2である)
が、酸化ストレスを緩和することにより、原核細胞と真核細胞の生存能力を高めることを見出したものである。
Zはカルボン酸およびその医薬的に許容される塩またはエステルから選ばれ、nは1または2である)が、有益な薬理学的活性を示すことを見出したものである。
。
− ポリ3−ヒドロキシ酪酸を溶媒に、好ましくは加熱と撹拌下で、溶解して溶液を形成する工程;
− 該溶液に酸を加えて酸性化した溶液を形成する工程;
− 該酸性化した溶液を還流条件下で加熱してポリ3−ヒドロキシ酪酸を加水分解してオリゴマーを生成する工程;
− 所望により行う、オリゴマー化した酸をエステル化する工程;および
− 該オリゴマーを、所望によりエステル形態で、回収する工程。
化合物1と化合物2の調製
構造1の分子と構造2の分子を3−HBポリマーから分解により調製した。したがって、ポリ3−ヒドロキシ酪酸(PHB)を、Athlan et al. (1997)に開示される方法を若干改変した方法で解重合した。PHBの半グラムを35mlのジクロロエタン中で加熱・撹拌して溶解した。還流前に、75mgのp−トルエンスルホン酸と25mlのメタノールを加えた。方法を、最大収率が得られるように還流時間16時間に最適化した。5mMのアンモニウムアセテートで液−液抽出を2回行い、水相を回収して凍結乾燥した。
M. extorquens DSM13060(野生型;植物成長促進性の球果植物内生菌;Pirttila et al. 2000)をDM1培地(成長調整因子を含まないD1培地;Hohtola 1988, Pirttila et al. 2008)にて、室温で定常期(4日)まで成長させてから、細菌細胞を遠心分離と0.2mmフィルター(ニューハンプシャー州、キーン、Schleicher & Schuell製)による濾過で除去して、無菌の調整培地を得た。この調整培地を凍結乾燥し、0.1%のギ酸とアセトニトリルを用いるグラジエント フラッシュ クロマトグラフィー(Sepra C-18-E、50μm(Phenomenex)吸着材)で分画した。各画分中の化合物をLC−MSで分析した。調整DM1培地をセミ分取スケールHPLCで10個に分画し、各画分が最大1種の3−HBオリゴマーを含んでいた。
酵母株(gsh1Δ (YJL101c)とgsh2Δ (YOL049w); EUROSCARF製)をグリセロールストックからYEPD寒天プレート(1% w/vのBacto酵母エキス;2% w/vのBactoペプトン;2% w/vのD−グルコース;2% w/vの寒天)に画線し、+30℃で48時間インキュベートした。酵母前培養物をプレートから液体SG最少培地(0.67% w/vの酵母窒素塩基、アミノ酸無し;2% w/vのグルコースと以下の適切な補助栄養:ウラシル、0.02 mg/ml;アミノ酸、0.03 mg/ml)に接種して、+30℃でオービタルシェーカーにて180rpmで定常期(1.0〜1.2 OD600)まで成長させた。成長は分光光度測定法で600nm(OD600)で測定し、細胞密度を1.0 OD600に調節した後、最終密度0.25 OD600で各アッセイ反応に接種した。
アッセイ反応をMoore et al. (2006)にしたがって調製し、黒色の96穴ポリスチレンプレート(Thermo Scientific製、FluoroNunc)において、Victor3マルチラベルプレートリーダー(フィンランド国、トゥルク、PerkinElmer製)で分析した。各反応混合物は、170μlの9.28×10−8Mのフルオレセイン(FL)を含む75mMのリン酸ナトリウムバッファー(pH7.4)、30μlのブランクまたはサンプルまたはスタンダード、40μlの0.1990MのH2O2、および60μlの3.43mMのFeCl3を含んでおり、これらの成分は96穴プレートに同じ順番でピペットで加えた。Trolox標準(20、40、60、80および100μM)、グルタチオンの対照溶液、ビタミンC、3−HBモノマー(3−ヒドロキシ酪酸、3−HBA)(ミズーリ州、セントルイス、Sigma-Aldrich製)、および3−HBオリゴマーサンプルを、各アッセイ毎に新たに50%アセトン中に調製した。各反応を96穴プレートにピペットで3回加えた。蛍光発光を励起波長485nmと発光波長535nmで測定した。各ウェル当たりの読取り時間は0.1秒で、各プレートは3時間に亘り、1分毎に1回読取った。Trolox濃度の曲線下面積(AUC)とフルオレセインの崩壊曲線下のネット面積に基づき(Ou et al. 2001)、純粋化合物の回帰式を用いて、相対HOSC値を計算した。値をTrolox等量(TE)(1マイクロモルのTEが1マイクロモルのサンプルに対応する)として表現した。実験を3回繰り返した。
AUC = 0.5 + f1/f0 + f2/f0 + f3/f0 + ... + fi-1/f0 + 0.5(fi/f0)
f0 = 0分の時点での初期蛍光発光値
fi = 最終的な蛍光発光値
[(AUCサンプル − AUCブランク)/(AUCTrolox − AUCブランク)] × (Troloxのモル濃度/サンプルのモル濃度)]
ハーバーワイス反応で駆動されるフェントン反応による、鉄が触媒するヒドロキシルラジカル生成(Liochev 1999, Kehrer 2000):
Fe3+ + O・2− → Fe2+ + O2 (1)
Fe2+ + H2O2 → Fe3+ + OH− + OH・(フェントン反応) (2)
正味の反応(net reaction):
O・2− + H2O2 → O2 + OH− + OH・ (3)
生体の細胞における酸化ストレスの緩和を確認し、また、真核細胞におけるヒドロキシルラジカル消去のための細胞内標的タンパク質を同定するために、HOSCアッセイ(Moore et al. 2006)に基づいて酵母欠失変異体バイオアッセイを開発した。ヒドロキシルラジカルは、フェントン様(Fenton-like)Fe3+/H2O2反応において生理的pH(7.4)の条件下で生成した。元のアッセイの設定を、酵母細胞用に、ホスフェートで緩衝されたSG培地において調節し、pHとO2のレベルをSENBIT(登録商標)システム(Vasala et al. 2006)を用いてモニターした。過酸化水素の濃度を致死値より下のレベル(2.5mM)に最適化し、反応を適量のFeCl3(0.0646mM)で補い、・OH(OHラジカル)の定常的な流れを調製した。
ヨーロッパアカマツ(Pinus sylvestris L.)の茎頂(n=9〜13)を若い木(10年を超える樹齢)から集め、70%エタノールで1分間、6%Ca(ClO)2で20分間、それぞれ表面滅菌し、滅菌水で入念に充分に3回洗浄した。滅菌水による洗浄の後、茎頂(芽)を層流フード内で無菌状態で剥き取り、培地に置いた。マツ茎頂を、8時間/16時間の光周期の下、+25±1℃で、一般式Iの分子(式中、nは2〜10)の存在下および不存在下で成長させた。マツ組織の生存能力を、6週間、目視により(図3)、および1%(w/v)のアセトカルミン着色により、評価した。各試験化合物に基づく生存能力を生きた芽の数(百分率)で記録した。実験は、18〜31個のマツ茎頂を載せたペトリ皿の上で各オリゴマー(単量体から十量体まで)について2回行った。
nは1〜10、特に1〜5、たとえば1〜4、有利には1〜3、好ましくは1または2であり、
Zはエステルおよびカルボン酸またはその医薬的に許容される塩から選ばれる)
を含む組成物を、効率的な量、該対象に投与することによって行う方法。
nは1〜10、特に1〜5、たとえば1〜4、有利には1〜3、好ましくは1または2であり、
Zはエステル、特に式COOR(式中、Rはアルキル基、特にメチル、エチル、n−プロピル、i−プロピル、n−ブチル、sec−ブチルおよびtert−ブチルよりなる群から選ばれる低級アルキル基であり、該アルキル基は所望により1個または2個以上のハロゲン原子、酸素原子および硫黄原子などのヘテロ原子を含んでもよい)を有するエステルである)。
特許文献
WO 2008110034
US 20020013339
WO 2006020179
US 2009253781
WO 0004895
JP 2005065652
WO 2009089144
Athlan, A, Braud, C., Vert, M, (1997) Abiotic aging of water-soluble 3-hydroxybutyric acid oligomers as monitored by capillary zone electrophoresis. J. Environ. Polymer Degradation. 5, 243-247.
Berge SM, Bighley LD, Monkhouse DC (1977) Pharmaceutical salts. J. Pharm Sci, 66: 1-19.
Haces ML, Hernandez-Fonseca K, Medina-Campos ON, Montiel T, Pedraza-Chaverri J, Massieu L (2008) Antioxidant capacity contributes to protection of ketone bodies against oxidative damage induced during hypoglycemic conditions. Exp. Neurol. 211: 85?96.
Hohtola, A., (1988) Seasonal changes in explant viability and contamination of tissue cultures from mature Scots pine. Plant Cell, Tissue and Organ Culture. 15, 211-222.
Liochev, S. I. (1999). The mechanism of “Fenton-like” reactions and their importance for biological systems. A biologist's view. Metal ions in biological systems, 36, 1.
Kehrer, J. P. (2000). The Haber-Weiss reaction and mechanisms of toxicity. Toxicology, 149(1), 43-50.
Moore J, Yin JJ, Yu LL (2006) Novel fluorometric assay for hydroxyl radical scavenging capacity (HOSC) estimation. J. Agric. Food Chem. 54: 617-26.
Ou B, Hampsch-Woodill M, Prior RL (2001) Development and validation of an improved oxygen radical absorbance capacity assay using fluorescein as the fluorescent probe. J. Agric. Food Chem. 49, 4619-4626.
Pirttila AM, Laukkanen H, Pospiech H, Myllyla R, Hohtola A (2000) Detection of intracellular bacteria in the buds of Scots pine (Pinus sylvestris L.) by in situ hybridization. Appl. Env. Microbiol. 66:3073-3077.
Pirttila AM, Podolich O, Koskimaki JJ, Hohtola E, Hohtola E (2008) Role of origin and endophyte infection in browning of bud-derived tissue cultures of Scots pine (Pinus sylvestris L.). Plant Cell, Tissue and Organ Culture. 95, 47?55.
Shimazu T, Hirschey MD, Newman J, He W, Shirakawa K, Le Moan N, Grueter CA, Lim H, Saunders LR, Stevens RD, Newgard CB, Farese Jr. RV, de Cabo R, Ulrich S, Akassoglou K, Verdin E (2013) Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science 339: 211-214.
Vasala A, Panula J, Bollok M, Illman L, Halsig C, Neubauer P. (2006) A new wireless system for decentralised measurement of physiological parameters from shake flasks. Microb. Cell. Fact. 5, 8.
Claims (10)
- Zがメチルエステルである、請求項1に記載の使用。
- 該眼科系疾患が網膜神経変性性疾患である、請求項1に記載の使用。
- 該疾患が網膜色素変性症、加齢性黄斑変性、緑内障、および糖尿病性網膜症よりなる群から選ばれる、請求項3に記載の使用。
- 該アルキル基が炭素数1〜6の低級アルキル基である、請求項1、3、4のいずれかに記載の使用。
- 該アルキル基がメチル、エチル、n−プロピル、i−プロピル、n−ブチル、sec−ブチルおよびtert−ブチルよりなる群から選ばれる、請求項5に記載の使用。
- nが1または2であり、Zが式COOR(式中、Rは炭素数1〜4の低級アルキル基である)を有するエステルである、請求項1、3〜5のいずれかに記載の使用。
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PCT/FI2015/050509 WO2016012657A1 (en) | 2014-07-21 | 2015-07-21 | Oligomeric forms of 3-hydroxybutyrate |
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FR2486072A1 (fr) * | 1980-07-03 | 1982-01-08 | Solvay | Procede pour la fabrication de l'acide b-hydroxybutyrique et de ses oligocondensats |
FR2641532B1 (fr) * | 1989-01-06 | 1991-03-29 | Solvay | Procede pour la preparation d'esters de l'acide (beta)-hydroxybutyrique |
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