JP2016145221A - アルキン類及び1,3−双極子機能性化合物とアルキン類を反応させる方法 - Google Patents
アルキン類及び1,3−双極子機能性化合物とアルキン類を反応させる方法 Download PDFInfo
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- JP2016145221A JP2016145221A JP2016030875A JP2016030875A JP2016145221A JP 2016145221 A JP2016145221 A JP 2016145221A JP 2016030875 A JP2016030875 A JP 2016030875A JP 2016030875 A JP2016030875 A JP 2016030875A JP 2016145221 A JP2016145221 A JP 2016145221A
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- 125000004964 sulfoalkyl group Chemical group 0.000 description 1
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- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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Abstract
Description
本発明は、米国国立衛生研究所の生物医学複合糖質の研究資源センターからの助成金による政府支援でなされた(認可番号P41−RR−5351)。
バイオ直交反応は、互いを材料する反応であって、各材料は、インビボで見出される官能基との制限された反応性を有するか、又は実質的に反応性がない。アジドと末端アルキンとの効率的反応は、即ち、「クリック」化学の最も幅広く研究された例であり、バイオ直交反応の有用な例として知られている。特に、末端アルキン類を用いてアジドの1,3−環化され、安定なチアゾール類が得られるCu(I)(例えば、Binder et al.,Macromol.Rapid Commun.2008,29:952−981)は、タンパク質、核酸、脂質、及び単糖類を含む様々な生体分子にタグを付けるために使用されている。付加環化はまた、活性に基づくタンパク質プロフィーリング、酵素活性のモニターリング、並びにマイクロアレイ及び低分子ライブラリーの化学的合成に使用されている。
一局面では、本発明は、アルキンを提供し、アルキンを製造する方法を提供する。一態様では、アルキンは、式:
例えば、驚くべきことに、本明細書に記載されている式Iで表されるアルキン(例えば、式中、XはC=O、C=N−OR3、C=N−NR3R4、CHOR3、又はCHNHR3を表し;各R3及びR4は、独立して、水素又は有機基を表す)は、他の歪んだ環状アルキン(例えば、式中、XはCH2を表す)よりも1,3−双極子機能性化合物に対する高い反応性を有することが見出されている。例えば、Codelli,et al.,J.Am.Chem.Soc.2008,130:11486−11493;Johnson et al.,Chem.Commun.2008,3064−3066;Sletten et al.,Organic Letters 2008,10:3097−3099;and Laughlin et al.,Science 2008,320:664−667を参照されたい。さらに、式Iで表される様々なアルケンを製造するための柔軟性を有する好都合な方法が本明細書中に開示されている。さらに、式Iで表されるアルキンは、アジドだけでなく、様々な他の1,3−双極子機能性化合物とも反応する能力を有する。
用語「含む」及びその変形は、これらが明細書及び特許請求の範囲に見られる限定された意味を有しない。本明細書で使用するとき、「1つの(a)」、「1つの(an)」、「その(the)」、「少なくとも1つの」、及び「1以上の」は交換可能に使用される。
銅不含及び迅速Huisgen付加環化による生細胞の代謝的に標識された糖コンジュゲートの視覚化
アジドは、生物系においてごく稀であり、バイオコンジュゲートのための魅力的な化学的操作として明らかとなっている(Kolb and Sharpless,Drug Discovery Today 2003,8:1128−1 137;Dedola et al.,Org.Biomol.Chem.2007 5:1006−1017;Moses and Moorhouse,Chem.Soc.Rev.2007,36:1249−1262;Nandivada et al.,Adv.Mater.2007,19:2197−2208;Wu and Fokin,Aldrichimica Acta 2007,40:7−17)。特に、安定したチアゾールを与える、末端アルケンを用いたCu1触媒の1,3−双極子付加環化(Rostovtsev et al.,Angew.Chem.2002,1 14:2708−271 1;Rostovtsev et al.,Angew.Chem.Int.Ed.2002,41:2596−2599;Tornoe et al.,J.Org.Chem.2002,67:3057−3064)は、様々な生体分子は、様々な生体分子のタグ化(Chin et al.,Science 2003,301:964−967;Wang et al.,J.Am.Chem.Soc.2003,125:3192−3193;Kho et al.,Proc.Natl.Acad.Sci USA 2004,101:12479−12484;Gierlich et al.,Org.Lett.2006,8:3639−3642;Link et al.,Proc.Natl.Acad.Sci USA 2006,103:10180−10185)、活性基準のタンパク質プロファイリング(Speers et al.,J.Am.Chem.Soc.2003,125:4686−4687)、並びにマイクロアレイ及び低分子ライブラリーの化学合成(Sun et al.,Bioconjugate Chem.2006,17:52−57)用に使用されている。
化学物質はAldrich及びFlukaから購入され、さらに精製せずに使用した。ジクロロメタンはCaH2から蒸留され、モレキュラーシーブ4Å上で保存された。ピリジンはP2O5から蒸留され、モレキュラーシーブ4Å上で保存された。THFはナトリウムから蒸留された。全ての反応は、アルゴン雰囲気下で無水条件で行われた。反応物は、Kieselgel 60 F254(Merck)上の薄層クロマトグラフィー(TLC)によってモニターされた。検出は、紫外線(UV)光(254nm)による試験によるか又はメタノール中の5%硫酸による炭化によった。フラッシュクロマトグラフィーは、シリカゲル(Merck、70〜230メッシュ)上で行われた。イアトロビーズ(Iatrobeads)(60μm)をBioscanから購入した。1H NMR(1D、2D)及び13C NMRは、Sunワークステーションを備えたVarian Merc 300分光計、及びVarian 500及び600MHz分光計で記録された。1H及び13C NMRスペクトルは、CDCl3で記録され、ケミカルシフト(δ)は、保護された化合物に対する内部標準として、溶媒ピーク(1H、δ7.24;13C、δ77.0)と比較したppmで与えられる。陰イオンマトリックス支援レーザー脱離イオン化−飛行時間(MALDI−TOF)は、マトリックスとしてジヒドロ安息香酸を用いて、VOYAGER−DE Applied Biosystemsで記録された。高分解能質量スペクトルは、マトリックスとしてTHF中の2,5−ジヒドロキシ−安息香酸を用いることによって、ポジティブモードでVOYAGER−DE Applied Biosystems上で得られた。
tert−ブチルジメチルシリル塩化物(3.0g、20mmol)は、CH2Cl2(20mL)及びピリジン(5mL)の混合物中の4(2.2g、10mmol)の撹拌された溶液に添加された。6時間室温で撹拌した後、反応混合物を水で希釈し、CH2Cl2(40mL)で抽出した。合わせた有機抽出物を水及びブラインで洗浄し、次に乾燥(MgSO4)させた。溶媒を減圧下で蒸発させ、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル、7/1、v/v)によって精製し、5(2.9g、87%)を得た。
CHCl3中の臭素(0.8g、5mmol)の溶液を0℃でCHCl3(30mL)中の5(1.7g、5mmol)に滴下した添加した。反応混合物は、反応が完了する(TLCによってモニターされる)まで、室温で12時間撹拌された。得られた混合物を水性飽和チオ硫酸ナトリウム溶液(15mL)で洗浄し、乾燥(MgSO4)させた。溶媒を減圧下で蒸発させ、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/CH2Cl2、7/1、v/v)によって精製し、6(1.2g、60%)を得た。
CH2Cl2(30mL)中の3(0.22g、1mmol)の溶液に、4−ニトロ−フェニルクロロギ酸塩(0.4g、2mmol)及びピリジン(0.4ml、5mmol)を添加した。4時間、周囲温度で撹拌後、得られた混合物をブライン(2×10mL)で洗浄し、有機層を乾燥(MgSO4)した。溶媒を減圧下で蒸発させ、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル、10/1、v/v)によって精製し、7(0.34g、89%)を得た。
DMF(10mL)中の8(37mg、0.1mmol)及びNEt3(30mg、0.3mmol)の溶液に7(39mg、0.1mmol)をアルゴン雰囲気下で添加された。 反応混合物を一晩周囲温度で撹拌後、溶媒を減圧下で蒸発させ、残渣をシリカゲルカラムクロマトグラフィー(CH2Cl2/CH3OH、20/1、v/v)によって精製し、9(44mg、71%)を得た。
3−ヒドロキシ−7,8−ジデヒドロ−1,2:5,6−ジベンゾシクロオクテン(2.2mg、0.01mmol)をCH3OH(1mL)に溶解し、アジド(3−アジドプロピル2,3,4,6−テトラ−O−アセテート−α−D−マンノピラノシド、1−O−[ジメチル(1,1,2−トリメチルプロピル)シリル]−4,6−O−イソプロピリジン−2−アジド−2−デオキシ−β−Dグルコピラノース、4,7,8−トリ−O−アセチル−5−アセトアミド−9−アジド−2,3−アンヒドロ−3,5,9−トリ−デオキシ−D−グリセロ−D−ガラクト−非−2−エノン酸メチルエステル、及び4−アジド−N−[(1,1−ジメチルエトキシ)カルボニル]−Lフェニルアラニン、1.0当量)に添加した。反応をTLCによってモニターし、反応混合物を30分間、室温で撹拌後、反応は完了した。溶媒を減圧下で蒸発させ、残渣をシリカゲルカラムクロマトグラフィーによって精製し、定量的収率でそれぞれ所望の生成物10〜13を得た。
CH2Cl2(100mL)中のジ−tert−ブチルジカーボネート(di−Boc)(6g、28mmol、0.5当量)の溶液をトリス(エチレングリコール)−1,8−ジアミン(7.6g、56mmol)及びジイソプロピルエチルアミン(10mL、57mmol)の混合物に、室温で2時間かけて滴下して添加した。反応混合物を6時間撹拌し、その後、真空中で濃縮した。フラッシュシリカゲルカラムクロマトグラフィー(CH2Cl2/CH3OH、10/1、v/v)による精製によって、N−Boc−3,6−ジオキサオクタン−1,8−ジアミン(4.1g、58%)を得た。
DMF(100ml)中のビタミンH(ビオチン)(2.2g,9mmol),O−ベンゾトリアゾール−1−イル−N,N,N’,N’−テトラメチルウロニウムヘキサフルオロホスフェート(HBTU)(3g、8mmol)、及びDIPEA(1.8mL、10mmol)の溶液を室温で10分間撹拌し、その後、N−Boc−3,6−ジオキサオクタン−1,8−ジアミン(1.5g、6mmol、1)の溶液に滴下して添加した。反応混合物を1時間室温で撹拌し、その後、DMFを真空中で除去し、油性残渣を得た。それをフラッシュシリカゲルカラムクロマトグラフィー(CH2Cl2/CH3OH、25/1、v/v)によって精製し、N−Boc−N’−ビオチニル−3,6−ジオキサオクタン−1,8−ジアミン(2.0g、90%)を得た。
N−Boc−N’−ビオチニル−3,6−ジオキサオクタン−1,8−ジアミン(1.9g、4mmol)をCH2Cl2(20mL)中の50%RFAに溶解し、1時間室温で撹拌した。溶媒を減圧下で蒸発させ、油性残渣を得て、それをフラッシュシリカゲルカラムクロマトグラフィー(CH2Cl2/CH3OH、10/1、v/v)によって精製し、7(1.3g、92%)を得た。
合成化合物2及び9をDMF中で再構成し、80℃で保存した。DMFの最終濃度は、毒性効果を避けるために0.56%を超えることはなかった。
重炭酸ナトリウム(1.5gL-1)、グルコース(4.5gL-1)、HEPES(10mM)、及びピルビン酸ナトリウム(1.0mM)を含むように調整され、ペニシリン(100umL-1)/ストレプトアビジン(100μgmL-1;Mediatech)及びウシ胎児血清(FBS、10%;Hycone)を補足された、L−グルタミン(2mM)を含むRPMI1640培地(ATCC)中でヒトJurkat細胞(クローンE6−1;ATCC)を培養した。湿度のある5%CO2雰囲気下、37℃で細胞を維持した。ペルアセチル化されたN−アジドアセチルマンノサミン(Ac4ManNAz;25μmolの最終濃度)の存在下で3日間、Jurkat細胞を培養し、細胞表面の糖タンパク質への対応するN−アジドアセチルシアル酸(SiaNAz)の代謝的な組込みをもたらした。アジドを有するJurkat細胞と未処理の対照細胞を標識バッファー(DPBS、FBS(1%)を補足されている)中の化合物2及び9(0〜100μmol濃度)とともに、0〜180分間室温でインキュベートした。標識バッファーで細胞を3回洗浄し、その後、フルオレセインをコンジュゲートさせたアビジン(Molecular Probes)とともに15分間4℃でインキュベートした。3回の洗浄及び細胞溶解後、細胞溶解物は、マイクロプレートリーダー(BMG Labtech)を用いて、蛍光強度(485ex/520em)について分析された。データ点は、3点測定で集め、3つの別々の実験を代表する。細胞の生存率は、トリパンブルーの排出を用いた手法で異なる点で評価された。
重炭酸ナトリウム(1.5gmL-1)を含むように調整され、ペニシリン(100umL−1)/ストレプトアビジン(100μgmL-1)及びFBS(10%)を補足された、L−グルタミン(2mM)を含むKaighn変法のHam’s F−12培地(F−12K)中でチャイニーズ・ハムスター・オバリー(CHO)細胞(クローンK1;ATCC)を培養した。湿度のある5%CO2雰囲気下、37℃で細胞を維持した。CHO細胞は、細胞表面の糖タンパク質に代謝的にSiaNAz(100μmol最終濃度)の存在下で3日間増殖させた。次に、アジドを有するCHO細胞及び未処理の対照細胞をカバーガラスに移し、36時間、元の培地中で培養した。CHO生細胞は、標識バッファー(DPBS、FBS(1%)を補足してある)で1時間4℃又は室温でビオチン化された化合物9(30マイクロモル濃度)で処理され、次に、AlexaFluor488(Molecular Probes)がコンジュゲートされたアビジンとともに15分間4℃でインキュベートされた。標識バッファーで細胞を3回洗浄し、ホルムアルデヒド(PBS中3.7%)で固定するか又は固定前に1時間37℃でインキュベートした。遠赤色蛍光TO−PRO−3色素(Molecular Probes)で核を標識した。細胞は、画像化前にPermaFlour(Thermo Electron Corporation)に備えつけた。初期の解析は、Zeiss Axioplan2蛍光顕微鏡で行った。共焦点画像は、60×(Na1.42)油浸対物レンズを用いて得た。光学的断片の積層をz次元で集めた。各対物のために計算された最適条件に基づくステップサイズは、0.25〜0.5μmであった(z−プロジェクション)。その後、各スタックを1つの画像にまとめられた。解析は、ImageJ 1.39fソフトウェア(National Institutes of Health,USA)及びAdobe Photoshop CS3拡張バージョン10.0(Adobe Systems Incorporated)を用いてオフラインで行い、それにより全ての画像を等しく処理した。
ビオチン及び切断可能なリンカーを含むアルキン試薬
アジドは、生物系においてごく稀であり、バイオコンジュゲートのための魅力的な化学的操作として明らかとなっている(Dedola et al.,Org.Biomol.Chem.2007,5,1006;Kolb and Sharpless,Drug D is.Today 2003,8,1 128;Moses and Moorhouse,Chem.Soc.Rev.2007,36,1249;Nandivada et al.,Adv.Mater.2007,19,2197;Wu and Fokin,Aldrichimica ACTA 2007,40,7;Agard et al.,ACS Chem.Biol.2006 1,644)。特に、末端アルケンを用いたアジドの1,3−双極子環化を触媒して、安定したトリアゾールを与えるCu(I)は、タンパク質、核酸、脂質、及び単糖を含む様々な生体分子にタグを付けるために使用されている(Chin et al.,Science 2003,301,964;Gierlich et al.,Org.Lett.2006,8,3639;Kho et al.,Proc.Natl.Acad.Sci.2004,101,12479;Link et al., Proc.Natl.Acad.Sci.2006,103,10180;Wang et al.,J.Am.Chem.Soc.2003,125,3192)。また、付加環化は、活性に基づくタンパク質プロファイリング(Speers et al., J. Am. Chem. Soc. 2003, 125, 4686)、酵素活性のモニターリング、並びにマイクロアレイ及び低分子ライブラリーの化学合成(Sun et al.,Bioconjugate Chem.2006,17,52)に使用されている。
生細胞及びナノ粒子の標識のための急速クリック反応
4−ジベンゾシクロオクチノールを調製し、アミン含有クリック試薬の調製のための化合物を使用する代替アプローチ
4−ジベンゾシクロオクチノール45は、代替の合成経路によって調製することができた(スキーム6;図14)。このようにして、既知のジベンゾスベレノン(41)は、CH2Cl2(20ml)中のBF3・OEt2の存在下、−10℃でチリメチルシリルジアゾメタンで処理され、6H−ジベンゾ[a,e]シクロオクタトリエン−5−オン(42)を良好な収率で得た。42のケトンは、エタノール及びTHFの混合物中で水素化ホウ素ナトリウムで還元され、アルコール43を得て、それは、二重結合のホウ素化によって4−ジベンゾシクロオクチノール45に変換することができ、その後、THF中のLDAを用いた処理によって、得られた化合物44を取り出した。化合物45は、Dess−Martin試薬の使用によって、対応するケトン46に酸化することができた。
6H−ジベンゾ[a,e]シクロオクタトリエン−5−オン(42)。CH2Cl2(30ml)中のジベンゾスベレノン41(2.888g、14.0mmol)及びBF3OEt2(2.59ml、21.0mmol)の撹拌溶液に、CH2Cl2(20ml)中のトリメチルシリルジアゾメタン(10.5ml、21.9mmol)野溶液を−10℃で1時間かけて滴下して添加した。混合物を−10℃で2時間撹拌し、その後、氷水上に注いだ。水層をCH2Cl2(3×100ml)で抽出し、有機層を合わせた。合わせた有機層をブラインで洗浄し、乾燥(MgSO4)させた。溶媒を減圧下で蒸発させ、粗製生成物は、シリカゲル上のフラッシュクロマトグラフィー(2:1〜1:2v/vヘキサン/CH2Cl2)によって精製し、青白い固体として生成物を得た(2.220g、72%)。
4−ジベンゾシクロオクチノール(61)の多数の類似体(63〜68)を調製し、ベンジルアジドによる付加環化の反応速度に対するこれらの修飾の影響は、1H NMRスペクトルのベンジル型プロトンシグナルの積分によって決定された。図15は、化合物61〜68の二次定数を示す。驚くべき見解は、化合物62は、ヒドロキシル機能を持たないが、類似の4−ジベンゾシクロオクチノール(61)よりも約70倍遅く反応するということであった。化合物63及び64におけるなどの61のヒドロキシルのアシル化は、反応速度のゆっくりとした減少をもたらした。また、化合物65などにおける、61のアルカリ化は反応のより遅い速度をもたらした。化合物66は、ジェミナル−二フッ化物を有するが、化合物61と同じ速度で反応した。興味深いことに、ケトン67は、1よりも僅かに高い反応速度で反応する。オキシム68は61と類似の反応を有する。これらの結果は、61のヒドロキシルの修飾が付加環化の速度に劇的に影響を与え得ることを示す。
70の合成。Et2O(100mL)のLiAlH4(0.38g、10mmol) 及びAlCl3(1.3g、10mmol)の撹拌溶液に、69(1.1g、5mmol)を添加した。ml). 反応を0℃で12時間保持し、その後、水(100ml)でクエンした。水層をエーテル(4×100ml)で抽出し、合わせた有機抽出物を水(100ml)及びブライン(100ml)で洗浄した。粗製生成物は、カラムクロマトグラフィー(ヘキサン/CH2Cl2、2/1、v/v)によって精製され、2つの70を得た(0.63g、61%;スキーム7;図16)。
安定したトリアゾールを与える、末端アルキンを有するアジドの1,3−双極子付加環化を触媒するCu(I)は、タンパク質、核酸、脂質、及び単糖を含む様々な生体分子にタグを付けるために使用されている。また、この反応は、高分子及びナノスケールの材料を修飾するために使用されている。非常に毒性のあるCu(I)を取り除くという潜在的な困難性は、生物学的又は医学的応用のための化合物又は材料のコンジュゲーション用に1,3−双極子付加環化の使用を複雑にする。アジドを用いた付加環化のために末端アルキンの変わりに4−ジベンゾシクロオクチノールを使用することにより、この問題が克服されるべきである。
PEG44−b−PCL2683の合成。PEG45−O−PCL23ブロック共重合体は記載されるように合成された。所定体積(12.0mL)のε−カプロラクトンモノマーをアルゴン雰囲気下、ある量(9.0g)のPEG81を含むフラスコに入れた。次に、1滴のSnOctを添加した。液体窒素温度まで冷却後、フラスコを12時間空にし、密封し、130℃で24時間放置した。合成されたポリマーをTHFに溶解し、冷ヘキサンによる沈殿によって回収し、真空下、室温で乾燥させた。PCLの重合度は、PEG81の重合度と比較して、1H NMRによって計算された。
4−ジベンゾシクロオクチノールは、ニトロン及びアシルジアゾ誘導体などの1,3−双極子とともに周囲温度で触媒及びプロモーターなしに反応することができ、バイオコンジュゲーション反応に独特の機会を与え得ることが分かった。
NMRによる秒オーダーの速度定数を計算するための方法。基質を別々に適切な溶媒に溶解し、6mMの濃度で1:1に混合した。転換率は、複数のケミカルシフトでの積分によって決定されるように、出発物質の消失及び2つの位置異性生成物の出現の両方によってモニターされた。反応の秒オーダーの速度定数は、1/[基質]対時間をプロットし、線形回帰による解析によって決定された。秒オーダーの速度定数は、決定された傾きの2分の1に対応する。
Claims (17)
- 式:
各R1は、独立して、水素、ハロゲン、ヒドロキシ、アルコキシ、硝酸エステル、亜硝酸エステル、硫酸エステル、及びC1−C10有機基からなる群から選択され;
各R2は、独立して、水素、ハロゲン、ヒドロキシ、アルコキシ、硝酸エステル、亜硝酸エステル、硫酸エステル、及びC1−C10有機基からなる群から選択され;
Xは、C=O、C=N−OR3、C=N−NR3R4、CHOR3、又はCHNHR3を表し;
各R3及びR4は、独立して、水素又は有機基を表し;並びに
R8は有機基を表す]
で表される化合物。 - 式:
各R1は、独立して、水素、ハロゲン、ヒドロキシ、アルコキシ、硝酸エステル、亜硝酸エステル、硫酸エステル、及びC1−C10有機基からなる群から選択され;
各R2は、独立して、水素、ハロゲン、ヒドロキシ、アルコキシ、硝酸エステル、亜硝酸エステル、硫酸エステル、及びC1−C10有機基からなる群から選択され;
Xは、C=O、C=N−OR3、C=N−NR3R4、CHOR3、又はCHNHR3を表し;
各R3及びR4は、独立して、水素又は有機基を表し;並びに
R8は有機基を表す]
で表される化合物。 - R8が生体分子を表す、請求項1又は2に記載の化合物。
- 生体分子が、ペプチド、タンパク質、糖タンパク質、核酸、脂質、単糖類、オリゴ糖類、多糖類、及びそれらの組み合わせからなる群から選択される、請求項3に記載の化合物。
- 式:
各R1は、独立して、水素、ハロゲン、ヒドロキシ、アルコキシ、硝酸エステル、亜硝酸エステル、硫酸エステル、及びC1−C10有機基からなる群から選択され;
各R2は、独立して、水素、ハロゲン、ヒドロキシ、アルコキシ、硝酸エステル、亜硝酸エステル、硫酸エステル、及びC1−C10有機基からなる群から選択され;
Xは、C=O、C=N−OR3、C=N−NR3R4、CHOR3、又はCHNHR3を表し;並びに
各R3、R4は及びR10は、独立して、水素又は有機基を表し、ただし、少なくとも1つのR10は有機基を表す]
で表される化合物。 - 式:
各R1は、独立して、水素、ハロゲン、ヒドロキシ、アルコキシ、硝酸エステル、亜硝酸エステル、硫酸エステル、及びC1−C10有機基からなる群から選択され;
各R2は、独立して、水素、ハロゲン、ヒドロキシ、アルコキシ、硝酸エステル、亜硝酸エステル、硫酸エステル、及びC1−C10有機基からなる群から選択され;
Xは、C=O、C=N−OR3、C=N−NR3R4、CHOR3、又はCHNHR3を表し;並びに
各R3、R4は及びR10は、独立して、水素又は有機基を表し、ただし、少なくとも1つのR10は有機基を表す]
で表される化合物。 - 有機基を表す少なくとも1つのR1が生体分子を表す、請求項5又は6に記載の化合物。
- 生体分子が、ペプチド、タンパク質、糖タンパク質、核酸、脂質、単糖類、オリゴ糖類、多糖類、及びそれらの組み合わせからなる群から選択される、請求項7に記載の化合物。
- 少なくとも2つの末端を含む、切断可能なリンカーフラグメント;
切断可能なリンカーフラグメントの第1末端に結合されたアルキンフラグメント;及び
切断可能なリンカーフラグメントの第2末端に結合されたビオチン化フラグメント
を含むアルキン。 - アルキンフラグメントが、歪んだ環状アルキンフラグメントを含む、請求項11に記載のアルキン。
- 少なくとも1つの重質量(heavy mass)アイソトープをさらに含む、請求項9又は10に記載のアルキン。
- 少なくとも1つの検出可能な標識をさらに含む、請求項9〜11のいずれか1項に記載のアルキン。
- 検出可能な標識が蛍光標識を含む、請求項12に記載のアルキン。
- 請求項9〜13のいずれか1項に記載の少なくとも1つのアルキンと少なくとも1つの1,3−機能性化合物との反応によって形成される複素環式化合物。
- 複素環式化合物を製造するための方法であって、
少なくとも1つの1,3−双極子機能性化合物と請求項9〜13のいずれか1項に記載の少なくとも1つのアルキンとを組み合わせ;及び
少なくとも1つの1,3−双極子機能性化合物と少なくとも1つのアルキンが複素環式化合物を形成するのに有効な条件下で反応できるようにする
ことを含む方法。 - アルキンを製造する方法であって:
式:
式XVで表される二臭化物を脱臭化水素化し、式:
各R1は、独立して、水素、ハロゲン、ヒドロキシ、アルコキシ、硝酸エステル、亜硝酸エステル、硫酸エステル、及びC1−C10有機基からなる群から選択され;
各R2は、独立して、水素、ハロゲン、ヒドロキシ、アルコキシ、硝酸エステル、亜硝酸エステル、硫酸エステル、及びC1−C10有機基からなる群から選択され;
Xは、C=O、C=N−OR3、C=N−NR3R4、CHOR3、又はCHNHR3を表し;並びに
各R3及びR4は、独立して、水素又は有機基を表す、方法。 - 式:
各R1は、独立して、水素、ハロゲン、ヒドロキシ、アルコキシ、硝酸エステル、亜硝酸エステル、硫酸エステル、及びC1−C10有機基からなる群から選択され;
各R2は、独立して、水素、ハロゲン、ヒドロキシ、アルコキシ、硝酸エステル、亜硝酸エステル、硫酸エステル、及びC1−C10有機基からなる群から選択され;
Xは、C=O、C=N−OR3、C=N−NR3R4、CHOR3、又はCHNHR3を表し;
R3は、共有結合した有機色素を含む有機基を表し;並びに
R4は、独立して、水素又は有機基を表す]
で表されるアルキン。
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US8133515B2 (en) | 2012-03-13 |
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