JP7303532B2 - 新規蛍光プローブ - Google Patents
新規蛍光プローブ Download PDFInfo
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- JP7303532B2 JP7303532B2 JP2018210101A JP2018210101A JP7303532B2 JP 7303532 B2 JP7303532 B2 JP 7303532B2 JP 2018210101 A JP2018210101 A JP 2018210101A JP 2018210101 A JP2018210101 A JP 2018210101A JP 7303532 B2 JP7303532 B2 JP 7303532B2
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- fluorescent probe
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Description
<1>以下の式(I)で表される化合物又はその塩を含む、ピューロマイシン感受性アミノペプチダーゼ(PSA)検出用蛍光プローブ:
Aは、アラニン残基であり、Bは、アミノ酸残基を表し、ここで、Aは隣接するN原子とアミド結合を形成して連結し、BはAとアミド結合を形成して連結しており、
Xは、Si(Ra)(Rb)、Ge(Ra)(Rb)、Sn(Ra)(Rb)、C(Ra)(Rb)、P(=O)(Ra)又はOを表し(ここで、Ra及びRbは、それぞれ独立に水素原子、アルキル基、又はアリール基を表す);
R1は、水素原子、又はそれぞれ置換されていてもよいアルキル基、カルボキシル基、エステル基、アルコキシ基、アミド基、及びアジド基よりなる群から独立に選択される1~4個の同一又は異なる置換基を表し;
R2は、水素原子、ヒドロキシル基、シアノ基、それぞれ置換されていてもよいアルキル基、アルコキシ基、アリール、又はヘテロアリールを表し;
R3及びR4は、それぞれ独立に、水素原子、ヒドロキシル基、ハロゲン原子、それぞれ置換されていてもよいアルキル基、スルホ基、カルボキシル基、エステル基、アミド基及びアジド基よりなる群から独立に選択される1~3個の同一又は異なる置換基を表し;
R5、R6、及びR7は、それぞれ独立に水素原子又はアルキル基を表し、
ここで、R6又はR7は、それぞれR4と一緒になって、それらが結合する窒素原子を含む環構造を形成してもよい。〕;
<2> Bが、アスパラギン残基又はリシン残基である、上記<1>に記載の蛍光プローブ;
<3>R2が、置換されていてもよい炭素数1~6個のアルキル基、又は置換されていてもよい炭素数1~6個のアルコキシ基である、上記<1>又は<2>に記載の蛍光プローブ;
<4>R2が、メチル基又はメトキシ基である、上記<1>~<3>のいずれか1に記載の蛍光プローブ;
<5>R1、R3、R4、R5、R6、及びR7が、いずれも水素原子である、上記<1>~<4>のいずれか1に記載の蛍光プローブ;
<6>上記<1>~<5>のいずれか1に記載の蛍光プローブを含む、がん細胞検出用組成物;
<7>前記がん細胞が、乳がん細胞である、上記<6>に記載の組成物;及び
<8>上記<1>~<5>のいずれか1項に記載の蛍光プローブを含む、ピューロマイシン感受性アミノペプチダーゼ(PSA)検出用キット
を提供するものである。
<9>上記<1>~<5>のいずれか1項に記載の蛍光プローブを測定対象試料と接触させる工程、及び、当該試料中に含まれるピューロマイシン感受性アミノペプチダーゼ(PSA)と前記蛍光プローブの反応による蛍光応答又は吸光度変化観測する工程を含むことを特徴とする、PSAの検出方法;
<10>蛍光イメージング手段を用いて前記蛍光応答を可視化することを特徴とする、上記<9>に記載の検出方法;
<11>前記測定対象試料が、ピューロマイシン感受性アミノペプチダーゼ(PSA)が発現している細胞である、上記<9>又は<10>に記載の方法;
<12>前記細胞が、がん細胞である、上記<11>に記載の方法;
<13>前記がん細胞が、乳がん細胞である、上記<12>に記載の方法
を提供するものである。
本発明の蛍光プローブでは、光誘起電子移動(PET:Photoinduced electron transfer)を用いた蛍光制御によって、PSA酵素活性を検出するものである。より詳細には、以下のスキームに示すように、キサンテン環の3位の側鎖に「A-B」のアミノ酸残基(ペプチド鎖)が連結している状態では、励起光を照射してもキサンテン環部位の電子受容性が高いため、ベンゼン環部位からの電子移動によって消光している状態である。これに対し、蛍光プローブ分子がPSAと反応することによって、側鎖の「A-B」ペプチド鎖が加水分解により切断され、3位がアミノ基に変化した場合には、キサンテン環部位の電子受容性が低下し、その結果、蛍光発光が観測されることとなる。
の種類及び当該キサンテン骨格に連結するベンゼン環の置換基(R1及びR2)の種類を調整することで、「A-B」切断による蛍光発光を、蛍光波長が600nm以上の赤色領域の蛍光とすることができるという特徴を有するものである。これにより、がん細胞等の存在を赤色蛍光応答として検出することが可能となる。
A)本発明の蛍光プローブを測定対象試料と接触させる工程;及び、
B)当該試料中に含まれるピューロマイシン感受性アミノペプチダーゼ(PSA)と前記蛍光プローブの反応による蛍光応答又は吸光度変化観測する工程
を含むことによって、PSAを発現している標的細胞のみを特異的に蛍光応答として検出又は可視化することができる。
本発明の検出方法においては、上記蛍光プローブを含むPSA検出用キットを用いることが好ましい。当該キットにおいて、通常、本発明の蛍光プローブは溶液として調製されているが、例えば、粉末形態の混合物、凍結乾燥物、顆粒剤、錠剤、液剤など適宜の形態の組成物として提供され、使用時に注射用蒸留水や適宜の緩衝液に溶解して適用することもできる。
以下に示す反応スキームに従い、キサンテン環の3位に種々の組み合わせのジペプチドを導入した、蛍光プローブ化合物を合成した。ここでは、まず反応スキーム(General Procedure)について説明した後、特定のジペプチドを有する個々の化合物の合成について説明する。
上述の反応スキームに従い、側鎖にAsn-Ala(NA)を有する本発明の蛍光プローブ化合物(NA-2-Me SiR600)を以下のとおり合成した。
1H-NMR (300 MHz, CD2Cl2) δ: 0.40 (d, 3H, J = 2.9 Hz), 0.56 (d, 3H, J = 5.9 Hz), 1.46 (d, 3H, J = 6.6 Hz), 2.36 (s, 3H), 3.58 (br, 2H), 4.20 (t, 1H, J = 6.6 Hz), 4.42 (d, 2H, J = 7.3 Hz), 4.43-4.46 (m, 1H), 5.66 (s, 1H), 5.95 (d, 1H, J = 7.3 Hz), 6.60 (dd, 1H, J = 8.4, 2.6 Hz), 6.88 (d, 1H, J = 8.1 Hz), 6.92 (d, 1H, J = 2.2 Hz), 7.00-7.10 (m, 4H), 7.17-7.18 (m, 1H), 7.26-7.28 (m, 2H), 7.31-7.34 (m, 1H), 7.38 (t, 2H, J = 7.0 Hz), 7.55-7.61 (m, 2H), 7.76-7.81 (m, 2H), 7.89 (s, 1H), 8.58 (s, 1H).
13C-NMR (75 MHz, CD2Cl2, isomer mixture) δ: -0.57, -0.53, -0.33, 18.72, 20.77, 47.46, 50.35, 51.71, 67.43, 117.29, 119.16, 120.31, 121.63, 124.50, 125.35, 125.41, 126.27, 126.56, 127.44, 128.08, 130.12, 130.43, 130.95, 131.58, 133.93, 134.55, 135.24, 135.28, 135.66, 138.65, 141.61, 144.01, 144.22, 144.46, 145.50, 146.39, 156.73, 171.21.
HRMS (ESI+): calcd for [M+H]+, 638.28389 ; found, 638.28361 (-0.28 mmu)
1H-NMR (400 MHz, CD3OD) δ: 0.58 (s, 3H), 0.60 (s, 3H), 1.49 (d, 3H, J = 7.3 Hz), 2.04 (s, 3H), 2.78-2.87 (m, 1H), 2.94-3.02 (m, 1H), 4.22 (dd, 1H, J = 8.5, 4.8 Hz), 4.54 (q, 1H, J = 7.2 Hz), 6.77 (dd, 1H, J = 9.8, 2.5 Hz), 7.09 (d, 1H, J = 9.1 Hz), 7.17 (d, 1H, J = 7.3 Hz), 7.31 (d, 1H, J = 10.1 Hz), 7.38-7.46 (m, 3H), 7.51 (t, 1H, J = 7.3 Hz), 7.60-7.66 (m, 1H), 8.24-8.29 (m, 1H)
13C-NMR (100 MHz, CD3OD) δ: -1.96, -1.68, 17.80, 19.56, 36.23, 51.15, 51.57, 120.29, 122.07, 126.75, 127.01, 128.38, 130.20, 130.51, 131.16, 131.58, 136.06, 137.00, 138.71, 139.28, 144.01, 144.51, 147.36, 156.11, 162.41, 169.62, 169.76, 173.25, 173.65.
HRMS (ESI+): calcd for [M+H]+, 528.24309 ; found, 528.24304 (-0.05 mmu)
上述の反応スキームに従い、側鎖にAsn-Ala(NA)を有する本発明の蛍光プローブ2(NA-2-OMe SiR600)を以下のとおり合成した。蛍光プローブ2は、式(I)におけるR2に相当するベンゼン環上の置換基がメトキシである点で、蛍光プローブ1(NA-2-Me SiR600)と相違する。
上記化合物1におけるベンゼン環上の置換基をメチルからメトキシに変えた
化合物9(Leuco-2-OMe SiR600)を以下のとおり合成した。
1H-NMR (300 MHz, CD2Cl2) δ: 0.50 (s, 3H), 0.57 (s, 3H), 3.65 (s, 4H), 3.98 (s, 3H), 6.04 (s, 1H), 6.64 (dd, 2H, J = 8.1, 2.2 Hz), 6.73-6.84 (m, 2H), 6.90-6.94 (m, 1H), 6.94 (d, 2H, J = 2.2 Hz), 7.06-7.12 (m, 1H), 7.20 (d, 2H, J = 8.1 Hz).
13C-NMR (75 MHz, CD2Cl2) δ: -0.69, 0.71, 45.91, 55.88, 111.55, 117.22, 119.35, 120.91, 126.87, 129.99, 130.82, 134.79, 137.68, 139.98, 144.43, 156.16
HRMS (ESI+): calcd for [M+H]+, 361.17361 ; found, 361.17301 (-0.60 mmu)
1H-NMR (400 MHz, CD2Cl2) δ: 0.46 (d, 3H, J = 1.8 Hz), 0.53 (d, 3H, J = 3.2 Hz), 1.45 (d, 3H, J = 6.9 Hz), 3.67 (br, 2H), 3.95 (s, 3H), 4.23 (t, 1H, J = 6.9 Hz), 4.44 (d, 3H, J = 6.9 Hz), 5.71 (s, 1H), 6.08 (s, 1H), 6.64 (d, 1H, J = 7.3 Hz), 6.71-6.79 (m, 2H), 6.91 (d, 2H, J = 7.8 Hz), 7.06-7.10 (m, 1H), 7.19 (d, 1H, J = 8.2 Hz), 7.28 (d, 2H, J = 6.4 Hz), 7.34-7.46 (m, 4H), 7.57-7.61 (m, 2H), 7.74-7.79 (m, 3H), 8.32 (s, 1H)
13C-NMR (100 MHz, CD2Cl2, isomer mixture) δ: -0.74, 0.63, 18.58, 46.39, 47.54, 51.75, 55.87, 67.44, 111.58, 117.38, 119.35, 120.33, 120.95, 121.73, 124.65, 125.38, 125.42, 127.15, 127.47, 128.10, 130.04, 130.56, 130.85, 134.50, 135.04, 135.67, 136.89, 139.37, 141.66, 144.17, 144.25, 144.55, 146.23, 156.15, 156.71, 170.96.
HRMS (ESI+): calcd for [M+Na]+, 676.26075 ; found, 676.26088 (0.13 mmu)
1H-NMR (400 MHz, CD3OD, isomer mixture) δ: 0.47 (s, 0.6H), 0.57 (s, 2.4H), 0.60 (d, 3H, J = 3.2 Hz), 1.49 (d, 2.7H, J = 7.3 Hz), 1.62 (d, 0.3H, J = 6.8 Hz), 2.66 (br, 0.2H), 2.77-2.87 (m, 0.9H), 2.96-3.02 (m, 0.9H), 3.09 (s, 0.6H), 3.73 (s, 2.4H), 4.06-4.25 (m, 1H), 4.49-4.57 (m, 1H), 6.69 (d, 0.2H, J = 4.0 Hz), 6.76 (d, 0.8H, J = 4.8Hz), 7.09-7.26 (m, 4H), 7.32 (d, 0.2H, J = 4.2 Hz), 7.38-7.42 (m, 1.8H), 7.53 (s, 0.2H), 7.59-7.68 (m, 1.6 H), 7.87-7.91 (m, 0.2H), 8.14 (s, 0.1H), 8.23 (br, 1H)
13C-NMR (100 MHz, CD3OD) δ: -1.91, -1.66, 17.83, 36.23, 51.17, 51.57, 56.25, 112.51, 119.88, 121.64, 121.90, 126.52, 128.09, 128.26, 131.46, 131.67, 132.27, 136.56, 138.76, 143.68, 144.28, 147.93, 156.11, 158.10, 162.39, 168.37, 169.59, 173.27, 173.60
HRMS (ESI+): calcd for [M+H]+, 544.23800 ; found, 544.23644 (-1.57 mmu)
実施例1で合成した蛍光プローブのライブラリーを用いて、ヒト乳がん手術検体におけるスクリーニングを実施した。初めに手術検体から腫瘍部位と正常部位に分けてライセートを作成し、A-B部位のペプチド鎖が異なる各プローブをそれぞれのライセートと反応させて蛍光強度変化を測定し、腫瘍部位由来のライセートで充分な蛍光上昇を示し、かつ高いT/N比(Tumor to Normal ratio)を示した36種の蛍光プローブを候補プローブとして選出した。
蛍光プローブ1について、手術検体の腫瘍部位から作成したライセートを用いて、DEG(diced electrophoresis gel)アッセイを行ったところ、活性の高い単一のスポットが観測された(図3(a))。このスポットに注目してPMF (Peptide Mass Fingerprinting)解析を行った。その結果、蛍光プローブ1の代謝酵素としてピューロマイシン感受性アミノペプチダーゼ(PSA)が同定された。同定されたPSAについて精製酵素を用いて蛍光プローブ1と反応させたところ、迅速な蛍光上昇を示した(図3(b))。これらの結果より、蛍光プローブ1がPSAをバイオマーカー酵素とする乳がん検出蛍光プローブとして有効であることが分かった。
実施例1で合成した蛍光プローブ1(化合物8:NA-2-Me SiR600)及び蛍光プローブ2(化合物11:NA-2-OMe SiR600)について、吸収及び蛍光スペクトルを測定し、また、量子収率を算出した。いずれも、蛍光プローブ濃度は1μMとし、0.1M リン酸Naバッファー(pH7.4、0.1%DMSO)溶液を用いた。
PSAに対する赤色蛍光プローブとして機能することが示された蛍光プローブ2と、GGTに対する蛍光応答を示すことが知られている乳がん検出緑色蛍光プローブ(gGlu-HMRG)とを併用して、乳がんのマルチカラーイメージングを試みた。gGlu-HMRGは、以下の構造を有する蛍光プローブであり、その合成法等は、Y.Uranoら、Sci. Transl. Med.,vol.3, pp.110ra119、2011年(非特許文献1)に開示されている。
Claims (11)
- 以下の式(I)で表される化合物又はその塩を含む、ピューロマイシン感受性アミノペプチダーゼ(PSA)検出用蛍光プローブ:
Aは、アラニン残基であり、Bは、アスパラギン残基又はリシン残基であり、ここで、Aは隣接するN原子とアミド結合を形成して連結し、BはAとアミド結合を形成して連結しており、
Xは、Si(Ra)(Rb)、Ge(Ra)(Rb)、Sn(Ra)(Rb)、C(Ra)(Rb)、P(=O)(Ra)又はOを表し(ここで、Ra及びRbは、それぞれ独立に水素原子、アルキル基、又はアリール基を表す);
R1は、水素原子、又はそれぞれ置換されていてもよいアルキル基、カルボキシル基、エステル基、アルコキシ基、アミド基、及びアジド基よりなる群から独立に選択される1~4個の同一又は異なる置換基を表し;
R2は、置換されていてもよいC1-C4アルコキシ基を表し;
R3及びR4は、それぞれ独立に、水素原子、ヒドロキシル基、ハロゲン原子、それぞれ置換されていてもよいアルキル基、スルホ基、カルボキシル基、エステル基、アミド基及びアジド基よりなる群から独立に選択される1~3個の同一又は異なる置換基を表し;
R5、R6、及びR7は、それぞれ独立に水素原子又はアルキル基を表し、
ここで、R6又はR7は、それぞれR4と一緒になって、それらが結合する窒素原子を含む環構造を形成してもよい。〕。 - R2が、メトキシ基である、請求項1に記載の蛍光プローブ。
- R1、R3、R4、R5、R6、及びR7が、いずれも水素原子である、請求項1又は2に記載の蛍光プローブ。
- 請求項1~3のいずれか1項に記載の蛍光プローブを含む、がん細胞検出用組成物。
- 前記がん細胞が、乳がん細胞である、請求項4に記載の組成物。
- 請求項1~3のいずれか1項に記載の蛍光プローブを含む、ピューロマイシン感受性アミノペプチダーゼ(PSA)検出用キット。
- 請求項1~3のいずれか1項に記載の蛍光プローブを測定対象試料と接触させる工程、及び、当該試料中に含まれるピューロマイシン感受性アミノペプチダーゼ(PSA)と前記蛍光プローブの反応による蛍光応答又は吸光度変化観測する工程を含むことを特徴とする、PSAの検出方法。
- 蛍光イメージング手段を用いて前記蛍光応答を可視化することを特徴とする、請求項7に記載の検出方法。
- 前記測定対象試料が、ピューロマイシン感受性アミノペプチダーゼ(PSA)が発現している細胞である、請求項7又は8に記載の方法。
- 前記細胞が、がん細胞である、請求項9に記載の方法。
- 前記がん細胞が、乳がん細胞である、請求項10に記載の方法。
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