JPWO2018043579A1 - ホスファローダミン化合物若しくはその塩、並びにそれを用いた蛍光色素 - Google Patents
ホスファローダミン化合物若しくはその塩、並びにそれを用いた蛍光色素 Download PDFInfo
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- JPWO2018043579A1 JPWO2018043579A1 JP2018537354A JP2018537354A JPWO2018043579A1 JP WO2018043579 A1 JPWO2018043579 A1 JP WO2018043579A1 JP 2018537354 A JP2018537354 A JP 2018537354A JP 2018537354 A JP2018537354 A JP 2018537354A JP WO2018043579 A1 JPWO2018043579 A1 JP WO2018043579A1
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- compound
- phospharhodamine
- substituted
- salt
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 122
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- 125000003118 aryl group Chemical group 0.000 claims abstract description 34
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 26
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 10
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 6
- 238000002372 labelling Methods 0.000 claims description 60
- 108090000623 proteins and genes Proteins 0.000 claims description 59
- 102000004169 proteins and genes Human genes 0.000 claims description 59
- 239000003795 chemical substances by application Substances 0.000 claims description 50
- 125000003545 alkoxy group Chemical group 0.000 claims description 14
- 150000001412 amines Chemical group 0.000 claims description 13
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 3
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- LIZDKDDCWIEQIN-UHFFFAOYSA-N 6-[2-[5-(3-ethyl-1,1-dimethyl-6,8-disulfobenzo[e]indol-2-ylidene)penta-1,3-dienyl]-1,1-dimethyl-6,8-disulfobenzo[e]indol-3-ium-3-yl]hexanoate Chemical compound C1=CC2=C(S(O)(=O)=O)C=C(S(O)(=O)=O)C=C2C(C2(C)C)=C1N(CC)\C2=C\C=C\C=C\C1=[N+](CCCCCC([O-])=O)C2=CC=C(C(=CC(=C3)S(O)(=O)=O)S(O)(=O)=O)C3=C2C1(C)C LIZDKDDCWIEQIN-UHFFFAOYSA-N 0.000 description 9
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical group O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- RKHXQBLJXBGEKF-UHFFFAOYSA-M tetrabutylphosphanium;bromide Chemical compound [Br-].CCCC[P+](CCCC)(CCCC)CCCC RKHXQBLJXBGEKF-UHFFFAOYSA-M 0.000 description 1
- IBWGNZVCJVLSHB-UHFFFAOYSA-M tetrabutylphosphanium;chloride Chemical compound [Cl-].CCCC[P+](CCCC)(CCCC)CCCC IBWGNZVCJVLSHB-UHFFFAOYSA-M 0.000 description 1
- HWCKGOZZJDHMNC-UHFFFAOYSA-M tetraethylammonium bromide Chemical compound [Br-].CC[N+](CC)(CC)CC HWCKGOZZJDHMNC-UHFFFAOYSA-M 0.000 description 1
- YMBCJWGVCUEGHA-UHFFFAOYSA-M tetraethylammonium chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC YMBCJWGVCUEGHA-UHFFFAOYSA-M 0.000 description 1
- 229940073455 tetraethylammonium hydroxide Drugs 0.000 description 1
- LRGJRHZIDJQFCL-UHFFFAOYSA-M tetraethylazanium;hydroxide Chemical compound [OH-].CC[N+](CC)(CC)CC LRGJRHZIDJQFCL-UHFFFAOYSA-M 0.000 description 1
- DDFYFBUWEBINLX-UHFFFAOYSA-M tetramethylammonium bromide Chemical compound [Br-].C[N+](C)(C)C DDFYFBUWEBINLX-UHFFFAOYSA-M 0.000 description 1
- RXMRGBVLCSYIBO-UHFFFAOYSA-M tetramethylazanium;iodide Chemical compound [I-].C[N+](C)(C)C RXMRGBVLCSYIBO-UHFFFAOYSA-M 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- RLZMYANQLOCZOB-UHFFFAOYSA-M tributyl(methyl)phosphanium;iodide Chemical compound [I-].CCCC[P+](C)(CCCC)CCCC RLZMYANQLOCZOB-UHFFFAOYSA-M 0.000 description 1
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 125000003960 triphenylenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C3=CC=CC=C3C12)* 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 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
- 239000008096 xylene Substances 0.000 description 1
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Abstract
Description
で表されるホスファローダミン化合物又はその塩。
で表される、項1又は2に記載のホスファローダミン化合物又はその塩。
で表される構造を末端に有する基である、項5に記載のホスファローダミン化合物又はその塩。
を備える、タンパク質標識化方法。
本発明のホスファローダミン化合物又はその塩は、一般式(1):
で表される化合物又はその塩である。この一般式(1)で表されるホスファローダミン化合物又はその塩は、文献未記載の新規化合物である。
で表される基が好ましい。
で表される構造を末端に有する基が好ましい。
等が挙げられる。
が好ましい。
等で表されるホスファローダミン化合物、又はその塩が好ましい。
本発明のホスファローダミン化合物又はその塩は、特に制限されず、例えば、R6及びR7が水素原子であるホスファローダミン化合物(1)は、以下の反応式1:
にしたがって合成することができる。
にしたがって合成することができる。この際、R11としてアミン反応性基又はチオール反応性基を導入すれば、タンパク質標識剤として機能することもできる。
本工程では、例えば、有機溶媒中で、上記反応式1及び2における化合物(3)と、有機リチウム化合物とを反応させた後に、有機リン化合物を添加し、次いで、過酸化水素を添加することにより、所望の環化反応を進行させることができる。
本工程では、例えば、有機溶媒中で、上記反応式1及び2における化合物(4)に対して、塩基性触媒及び相間移動触媒の存在下に酸化反応を引き起こすことができる。
本工程では、例えば、有機溶媒中で、有機リチウム化合物及び酸化剤の存在下に、上記反応式1における化合物(5)と所望のハロゲン化芳香族化合物とを反応させることで、求核付加反応を引き起こすことができる。なお、本工程では、有機リチウム化合物及び所望のハロゲン化芳香族化合物の代わりに、所望のグリニャール試薬を使用することによっても、同様の反応を進行することができる。グリニャール試薬は、あらかじめ合成することもでき、上記ハロゲン化芳香族化合物を用いて、常法により系中で合成することもできる。
R8−X3 (6)
[式中、R8は前記に同じである。X3はハロゲン原子を示す。]
で表される化合物であり、化合物(5)に基R8を導入することができる。
等が挙げられる。
本工程では、例えば、有機溶媒中で、有機リチウム化合物及び酸化剤の存在下に、上記反応式1における化合物(5)と所望のハロゲン化芳香族化合物とを反応させることで、求核付加反応を引き起こし、さらに、別途酸化剤を用いて酸化反応を起こすことで、化合物(1A)を得ることができる。なお、本工程では、上記(2−3)とは異なり、有機リチウム化合物及び所望のハロゲン化芳香族化合物の代わりに、所望のグリニャール試薬を使用した場合には、ほとんど反応が進行しない。
で表される化合物が好ましい。
等が挙げられる。
R11として反応性基を導入する場合、常法により、化合物(1A)のカルボキシ基を所望の反応性基に置換することができる。この際、例えば、カルボジイミド系縮合剤(N,N’-ジシクロヘキシルカルボジイミド、1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド塩酸塩、ジイソプロピルカルボジイミド)、イミダゾール系縮合剤(カルボニルジイミダゾール、2-クロロ-1,3-ジメチルイミダゾリニウムクロリド)、トリアジン系縮合剤(4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド)、ホスホニウム系縮合剤(ベンゾトリアゾール-1-イルオキシ-トリスジメチルアミノホスホニウム塩、ヘキサフルオロリン酸(ベンゾトリアゾール-1-イルオキシ)トリピロリジノホスホニウム)、ウロニウム系縮合剤({{[(1-シアノ-2-エトキシ-2-オキソエチリデン)アミノ]オキシ}-4-モルホリノメチレン}ジメチルアンモニウムヘキサフルオロリン酸塩、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リン酸塩、O-(7-アザ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リン酸塩、N,N,N’,N’-テトラメチル-O-(N-スクシンイミジル)ウロニウムテトラフルオロボレート(TSTU))等の縮合剤を使用することができる。例えば、TSTUを使用した場合には、アミン反応性基としてスクシンイミド基を導入し、タンパク質標識剤(特に抗体標識剤)として機能することができる。
本発明の蛍光色素は、上記の本発明のホスファローダミン化合物又はその塩からなる。
本発明のタンパク質標識キットは、本発明のタンパク質標識剤(特に抗体標識剤)を含有する。その他、必要に応じて、タンパク質(特に抗体)の標識に用いる際に使用するバッファー、培地、使用説明書等を含有することもできる。本発明のタンパク質標識キットを用いれば、タンパク質(特に抗体)を容易に標識することが可能である。使用できるバッファー、培地等は、従来から使用されている公知のものを採用することができる。
無水テトラヒドロフラン(THF; 50mL)中のビス(2-ブロモ-4-ジエチルアミノフェニル)メタン(化合物1; 5.15g, 11.0mmol)の溶液に、sec-ブチルリチウム(シクロヘキサン中の0.99M溶液, 22.2mL, 22mmol)を-78℃で30分間かけて添加し、得られた混合物を-78℃で1.5時間撹拌した。次いで、P,P-ジクロロフェニルホスフィン(1.49mL, 11.0mmol)をゆっくりと30分以上かけて添加し、混合物を一晩で室温まで昇温した。次いで、混合物を0℃まで冷却し、35%過酸化水素水(5mL)を添加した。得られた混合物を0℃で1時間撹拌し、飽和Na2SO3水溶液(35mL)を添加して反応をクエンチした。混合物をクロロホルムで4回抽出し、水及び飽和食塩水で洗浄し、無水Na2SO4で乾燥した。溶媒を蒸発させ、油状の残渣を50mLのジメチルスルホキシド(DMSO)に溶解させ、K2CO3粉末(4.56g, 33mmol)及びテトラブチルアンモニウムブロミド(TBAB; 89mg, 0.275mmol)を添加した。空気雰囲気下、室温で、得られた懸濁液を一晩激しく撹拌した。次いで、再度、K2CO3粉末(3.04g, 22mmol)及びTBAB(89mg, 0.275mmol)を添加し、懸濁液をさらに50℃で24時間撹拌した。混合物を水(150mL)で希釈し、冷ました。得られた黄色沈殿をろ過し、水で洗浄した。得られた固体をジクロロメタン(DCM)に溶解させ、層分離した。水層をDCMで5回抽出し、合わせた有機層を水で2回洗浄し、無水Na2SO4で乾燥した。溶媒を真空下に除去した後、残渣(5.35g)をトルエンから再結晶し、山吹色固体として化合物2を得た(2.18g, 44%)。再結晶により得られたろ液には、まだ化合物2と未酸化の前駆体2-Hが残存している。ろ液を真空下に濃縮し、残渣を60mLのTHFに溶解させた。NaOH粉末(720 mg)及びTBAB(97mg, 0.30mmol)をこの溶液に添加し、得られた懸濁液を、室温で空気雰囲気下に2時間激しく撹拌し、酸化を完了した。混合物を水で希釈し、DCMで4回抽出し、水で洗浄し、無水Na2SO4で乾燥した。溶媒を蒸発させた後に、生成物をシリカゲルカラムクロマトグラフィー(90/10 to 85/15 DCM/アセトン)により精製し、次いで、トルエン/ヘキサンから再結晶させ、化合物2を得た(836mg, 17%)。合計3.02 g(6.76mmol, 61%)の化合物2を山吹色結晶性固体として得た。
1H NMR (400 MHz, CDCl3) δ 8.27 (dd, J = 9.2, 6.1 Hz, 2H), 7.67-7.48 (m, 2H), 7.44-7.27 (m, 3H), 7.09 (dd, J = 14.7, 3.1 Hz, 2H), 6.82 (dd, J = 8.9, 2.8 Hz, 2H), 3.61-3.25 (m, 8H), 1.14 (t, J = 7.3 Hz, 12H). 13C{1H} NMR (100 MHz, CDCl3) δ 180.2 (d, JCP = 7.7 Hz, C), 150.5 (d, JCP = 12.5 Hz, C), 135.3 (d, JCP = 105.5 Hz, C), 134.8 (d, JCP = 95.8 Hz, C), 131.5 (d, JCP = 10.5 Hz, CH), 131.4 (d, JCP =2.9 Hz, CH), 130.4 (d, JCP = 10.6 Hz, CH), 128.6 (d, JCP = 12.4 Hz, CH), 123.9 (d, JCP = 6.7 Hz, C), 114.3 (s, CH), 111.5 (d, JCP = 7.6 Hz, CH), 44.6 (s, CH2), 12.5 (s, CH3). HRMS (ESI) m/z calcd. for C27H31N2O2PNa ([M+Na]+): 469.2015; found: 469.2015.
1H NMR (400 MHz, CDCl3) δ 7.64 (s, 2H), 4.10 (s, 2H), 2.43 (s, 6H), 1.37 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 161.8, 138.7, 131.1, 127.8, 126.4, 79.3, 67.8, 28.5, 23.9. HRMS (ESI) m/z calcd. for C13H17BrNO ([M+H]+): 282.0488; found: 282.0487.
窒素雰囲気下、4-ブロモ-3,5-ジメトキシ安息香酸(5.22g, 20.0mmol)、N,N’-ジシクロヘキシルカルボジイミド(DCC; 5.36g, 26.0mmol)、及びN,N-ジメチル-4-アミノピリジン(DMAP; 244mg, 2.00mmol)を60mLのジクロロメタンに溶解させた。ここに、ジクロロメタン(20mL)中のtert-ブチルアルコール(3.85g, 52.0mmol)の溶液を添加し、得られた混合物を室温で3日間撹拌した。白色沈殿をろ過により除去し、ろ液を減圧下に濃縮した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/DCM 3/2 to 1/2)で精製し、白色固体として化合物4を得た(3.34g, 10.5mmol, 53%)。
1H NMR (400 MHz, CDCl3) δ 7.20 (s, 2H), 3.95 (s, 6H), 1.61 (s, 9H). 13C{1H} NMR (125 MHz, CDCl3) δ 165.3, 157.0, 132.2, 106.3, 105.6, 81.9, 56.7, 28.3.
1H NMR (400 MHz, CD3OD) δ 7.80-7.40 (m, 10H), 7.28-7.18 (m, 1H), 7.18-7.08 (m, 2H), 6.97 (dd, J = 9.5, 2.8 Hz, 2H), 3.93-3.63 (m, 8H), 2.09 (2×s, 3H), 1.28 (2×t, J = 6.9 Hz, 12H). HRMS (ESI) m/z calcd. for C34H38N2OP (M+): 521.2716; found: 521.2707.
1H NMR (400 MHz, CD3OD) δ 7.86-7.61 (m, 5H), 7.56 (td, J = 7.6, 3.7 Hz, 2H), 7.41 (t, J = 7.6 Hz, 1H), 7.28 (t, J = 7.9 Hz, 2H), 7.13 (dd, J = 9.8, 6.1 Hz, 2H), 6.99 (dd, J = 9.8, 2.4 Hz, 2H), 3.77 (q, J = 6.9 Hz, 8H), 2.04 (s, 3H), 2.02 (s, 3H), 1.30 (t, J = 7.0 Hz, 12H). 13C{1H} NMR (100 MHz, CD3OD) δ 165.3 (d, JCP = 6.8 Hz, C), 155.2 (d, JCP = 12.5 Hz, C), 140.6 (d, JCP = 8.6 Hz, CH), 139.3 (d, JCP = 94.9 Hz, C), 137.5 (s, C), 136.7 (s, C), 136.5 (s, C), 134.6 (d, JCP = 2.9 Hz, CH), 133.9 (d, JCP = 109.3 Hz, C), 131.3 (d, JCP = 11.5 Hz, CH), 130.7 (d, JCP = 12.4 Hz, CH), 130.7 (s, CH), 129.1 (s, CH), 129.0 (s, CH), 123.9 (d, JCP = 6.7 Hz, C), 121.1 (d, JCP = 7.6 Hz, CH), 117.4 (s, CH), 47.7 (s, CH2), 20.0 (s, CH3), 19.8 (s, CH3), 13.1 (s, CH3). HRMS (ESI) m/z calcd. for C35H40N2OP (M+): 535.2873; found: 535.2868.
1H NMR (400 MHz, CD3OD) δ 7.82 (dd, J = 12.8, 7.9 Hz, 2H), 7.71-7.46 (m, 6H), 7.38-7.17 (m, 2H), 7.07-6.77 (m, 4H), 3.88-3.60 (m, 14H), 1.27 (t, J = 6.7 Hz, 12H). 13C{1H} NMR (100 MHz, CD3OD) δ 162.7 (d, JCP = 6.7 Hz, C), 159.2 (s, C), 158.8 (s, C), 155.1 (d, JCP = 12.5 Hz, C), 141.3 (d, JCP = 9.6 Hz, CH), 139.4 (d, JCP = 94.9 Hz, C), 134.3 (s, CH), 133.8 (d, JCP = 106.4 Hz, C), 133.3 (s, CH), 130.8 (d, JCP = 10.5 Hz, CH), 130.5 (d, JCP = 13.4 Hz, CH), 125.2 (d, JCP = 6.7 Hz, C), 119.9 (d, JCP = 7.7 Hz, CH), 116.7 (s, CH), 113.9 (s, C), 105.3 (s, CH), 105.2 (s, CH), 56.8 (s, CH3), 56.6 (s, CH3), 47.5 (s, CH2), 13.1 (s, CH3). HRMS (ESI) m/z calcd. for C35H40N2O3P (M+): 567.2771; found: 567.2766.
1H NMR (400 MHz, CD3OD) δ 7.95 (s, 1H), 7.93 (s, 1H), 7.78-7.61 (m, 5H), 7.56 (td, J = 7.5, 3.3 Hz, 2H), 7.09 (dd, J = 9.8, 6.1 Hz, 2H), 7.00 (dd, J = 9.8, 2.4 Hz, 2H), 3.77 (q, J = 6.7 Hz, 8H), 2.11 (s, 3H), 2.07 (s, 3H), 1.30 (t, J = 7.3 Hz, 12H). 13C{1H} NMR (100 MHz, CD3OD) δ 169.1 (s, C), 163.6 (d, JCP = 6.7 Hz, C), 155.2 (d, JCP = 12.5 Hz, C), 141.1 (s, C), 140.2 (d, JCP = 9.5 Hz, CH), 139.3 (d, JCP = 94.8 Hz, C), 138.3 (s, C), 137.5 (s, C), 134.6 (s, CH), 133.8 (d, JCP = 109.2 Hz, C), 133.1 (s, C), 131.3 (d, JCP = 10.6 Hz, CH), 130.7 (d, JCP = 12.5 Hz, CH), 130.2 (s, CH), 130.1 (s, CH), 123.3 (d, JCP = 6.7 Hz, C), 121.4 (d, JCP = 7.7 Hz, CH), 117.6 (s, CH), 47.7 (s, CH2), 20.0 (s, CH3), 19.8 (s, CH3), 13.1 (s, CH3). 31P{1H} NMR (162 MHz, CD3OD) δ 11.6. HRMS (ESI) m/z calcd. for C36H40N2O3P (M+): 579.2771; found: 579.2770.
1H NMR (400 MHz, CD3OD) δ 7.87-7.75 (m, 2H), 7.67-7.59 (m, 2H), 7.58-7.48 (m, 5H), 7.25 (dd, J = 9.5, 6.4 Hz, 2H), 6.94 (dd, J = 9.8, 2.4 Hz, 2H), 3.83 (s, 3H), 3.82 (s, 3H), 3.73 (q, J = 7.1 Hz, 8H), 1.28 (t, J = 7.0 Hz, 12H). 13C{1H} NMR (100 MHz, CD3OD) δ 168.7 (s, C), 160.8 (d, JCP = 6.7 Hz, C), 159.2 (s, C), 158.8 (s, C), 155.1 (d, JCP = 13.5 Hz, C), 141.0 (d, JCP = 8.6 Hz, CH), 139.4 (d, JCP = 93.9 Hz, C), 136.0 (s, C), 134.3 (s, CH), 133.8 (d, JCP = 108.0 Hz, C), 130.8 (d, JCP = 10.5 Hz, CH), 130.6 (d, JCP = 13.4 Hz, CH), 124.7 (d, JCP = 6.7 Hz, C), 120.2 (d, JCP = 7.6 Hz, CH), 118.4 (s, C), 116.9 (s, CH), 106.5 (s, CH), 106.4 (s, CH), 57.0 (s, CH3), 56.8 (s, CH3), 47.6 (s, CH2), 13.1 (s, CH3). HRMS (ESI) m/z calcd. for C36H40N2O5P (M+): 611.2669; found: 611.2666.
1H NMR (400 MHz, CD3OD) δ 8.07 (s, 1H), 8.05 (s, 1H), 7.81-7.61 (m, 5H), 7.56 (td, J = 7.6, 3.3 Hz, 2H), 7.08 (br s, 2H), 7.00 (d, J = 8.6 Hz, 2H), 3.78 (q, J = 5.5 Hz, 8H), 2.94 (s, 4H), 2.15 (s, 3H), 2.11 (s, 3H), 1.30 (t, J = 7.0 Hz, 12H). HRMS (ESI) m/z calcd. for C40H43N3O5P (M+): 676.2935; found: 676.2930.
市販の蛍光色素であるCy5.5(GE Healthcare)を比較例1の蛍光色素とした。
1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 4.8 Hz, 2H), 7.65-7.60 (m, 2H), 7.42-7.36 (m, 1H), 7.36-7.30 (m, 2H), 6.79 (d, J = 14.0 Hz, 2H), 3.52 (t, J = 8.6 Hz, 4H), 3.12-3.01 (m, 4H), 2.86 (s, 6H).
1H NMR (400 MHz, CD3OD) δ 7.80-7.86 (m, 2H), 7.56-7.61 (m, 2H), 7.54-7.48 (m, 2H), 7.31 (d, J = 14.8 Hz, 2H), 6.85-6.92 (m, 4H), 3.95-3.84 (m, 4H), 3.76 (s, 3H), 3.75 (s, 3H), 3.21 (s, 6H), 3.06-2.96 (m, 4H). HRMS (ESI) m/z calcd. for C33H32N2O3P (M+): 535.2145; found: 535.2128.
PR1(実施例1)、PR2(実施例2)、PR4(実施例4)及びPR6(実施例8)の吸収スペクトル及び蛍光スペクトルを測定した。具体的には、吸収スペクトルは、PBSバッファー水溶液(pH7.4)に各化合物を10-6M溶解させた試料溶液を用いて、Shimadzu UV-3150 spectrometerにより、解像度0.2nmで測定した。また、蛍光スペクトルは、解像度1nmのHitachi F-4500 spectrometerで、PBSバッファー水溶液(pH7.4)に各化合物を10-6M溶解させた試料溶液を用いて測定した。絶対蛍光量子収率は、Hamamatsu photonics PMA-11で測定した。結果を図1及び表1に示す。図1において、破線が吸収スペクトル、実線が蛍光スペクトルである。この結果、PR1、PR2及びPR4は、類似した光物理特性を有していた。また、PR6のように、ホスファローダミン骨格のπ共役を拡張することによって、吸収極大波長及び蛍光極大波長を70〜90nm程度長波長化することが可能であった。さらに、これら全ての化合物は水溶性である。このため、DMSOを共溶媒として添加することなく、測定試料を作製することができた。
PR1(実施例1)、PR2(実施例2)及びPR4(実施例4)の吸収スペクトル及び蛍光スペクトルを、様々なpHのバッファー水溶液中で測定した。pH3〜6の調整にはクエン酸/Na2HPO4バッファー水溶液を用い、pH7〜8の調整にはNa2HPO4/NaH2PO4バッファー水溶液を用い、pH9〜11の調整にはNa2CO3/NaHCO3バッファー水溶液を用いた。その他、吸収スペクトル及び蛍光スペクトルの測定方法は試験例1と同様に行った。
1mgのヤギ抗マウス抗体IgG(TCI, 1mg/vial, 防腐剤: 0.07% NaN3)を約0.5mLのPBSバッファー溶液(pH7.4)に溶解させ、さらに、PBSバッファー溶液(pH7.4)で希釈して全量を1.0mLとし、抗体溶液を得た。
蛍光色素を接合した抗体の退色を以下のように評価した。測定用試料としては、PR4-NHS(実施例6; DOL3.5, 27μg)、PR5-NHS(実施例7; DOL3.1, 20μg)、Cy5.5(比較例1; DOL2.3, 30μg)により接合したヤギ抗マウス抗体IgGを使用した。300Wキセノンランプを使用し、フィルターを使用せず、385〜750 nmの波長域で吸収強度を測定し、初期吸収強度が約0.1となるように調整した。各化合物の吸収強度及び蛍光強度について、時間経過にともなう維持率と、吸収スペクトル及び蛍光スペクトルとを図6に示す。図6の上図において、実線はPR4-NHS(実施例6; DOL3.5)、破線はPR5-NHS(実施例7; DOL3.1, 20μg)、一点鎖線はCy5.5(比較例1; DOL2.3)を使用した結果である。さらに、PR4-NHS(実施例6)、PR5-NHS(実施例7)及びCy5.5(比較例1)で標識したヤギ抗マウス抗体IgGを用いて10分間共焦点蛍光イメージングを行った結果を図7に示し、照射領域の平均蛍光強度を図8に示す。図8は細胞を染色した状態での蛍光強度の時間推移を評価した結果である。図8において、実線は(実施例6; DOL3.5, 27μg)、破線はPR5-NHS(実施例7; DOL3.1, 20μg)、一点鎖線はCy5.5(比較例1; DOL2.3, 30μg)を用いた結果である。この結果、細胞を染色した状態においても、本発明のホスファローダミン化合物は、従来の蛍光色素であるCy5.5と比較して、長時間にわたって抗体を蛍光させることができた。
PR5-NHSで標識したオリゴアルギニン(8量体)を用いて、ヒメツリガネゴケ(学名:Physcomitrella patens)の原糸体の蛍光イメージングを行った。
Claims (10)
- 前記R6及びR7がいずれも水素原子である、請求項1に記載のホスファローダミン化合物又はその塩。
- 前記R9及びR10がいずれも置換若しくは非置換アルキル基、又は置換若しくは非置換アルコキシ基である、請求項3に記載のホスファローダミン化合物又はその塩。
- 前記R11が、アミン反応性基又はチオール反応性基である、請求項3又は4に記載のホスファローダミン化合物又はその塩。
- 請求項1〜6のいずれかに記載のホスファローダミン化合物又はその塩からなる蛍光色素。
- 請求項5又は6に記載のホスファローダミン化合物又はその塩を用いたタンパク質標識剤。
- 請求項8に記載のタンパク質標識剤を含有する、タンパク質標識化キット。
- 請求項8に記載のタンパク質標識剤と、タンパク質とを反応させる工程
を備える、タンパク質標識化方法。
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