JPH06123740A - @(3754/24)mero) cyanine pigment for pprotein-labeling and pigment-labelled protein - Google Patents
@(3754/24)mero) cyanine pigment for pprotein-labeling and pigment-labelled proteinInfo
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- JPH06123740A JPH06123740A JP4272916A JP27291692A JPH06123740A JP H06123740 A JPH06123740 A JP H06123740A JP 4272916 A JP4272916 A JP 4272916A JP 27291692 A JP27291692 A JP 27291692A JP H06123740 A JPH06123740 A JP H06123740A
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- pigment
- bonded
- protein
- carbon
- cyanine
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Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は蛋白質標識用（メロ）シ
アニン色素、及び該色素を標識した蛋白質に関する。FIELD OF THE INVENTION The present invention relates to a (mero) cyanine dye for protein labeling, and a protein labeled with the dye.
【０００２】[0002]
【従来の技術】特定の酸素や蛋白質のような生体高分子
を検出する為に、蛋白質に色素等を標識することが一般
的に行なわれている。その際、蛋白質と同様に色素も水
溶性であることが望ましい。シアニン色素（またはメロ
シアニン色素）は、モル吸光係数（ε）が約１０5であ
り、近赤外に吸収を持ち、検出の際に生体由来の不純物
の影響をうけない（生体由来の不純物の多くは長波長に
吸収をもたないから）ことから標識色素として好ましく
用いられている。しかし、シアニン色素は一般にアルコ
ールには溶解するが水には難溶であるため、従来、シア
ニン色素の水溶性を増すためにカルボキシ基、スクシン
イミド基あるいはスルホン基などの極性基を有する誘導
体として標識用に用いていた。2. Description of the Related Art In order to detect a specific biopolymer such as oxygen or protein, it is common practice to label the protein with a dye or the like. At that time, it is desirable that the dye as well as the protein be water-soluble. Cyanine dye (or merocyanine dye) has a molar extinction coefficient (ε) of about 10 5 , has absorption in the near infrared, and is not affected by biological impurities during detection (most biological impurities are present). Has no absorption at long wavelengths) and is therefore preferably used as a labeling dye. However, since cyanine dyes are generally soluble in alcohol but poorly soluble in water, conventionally, in order to increase the water solubility of cyanine dyes, they are labeled as a derivative having a polar group such as a carboxy group, a succinimide group or a sulfone group. Was used for.
【０００３】[0003]
【発明が解決しようとしている問題点】シアニン色素の
極性基誘導体はおもに２つに分類され、その１つはＮ−
アルキル末端にカルボキシ基やスクシンイミド基を導入
した誘導体であるが水溶性はまだ十分ではなかった。も
う１つはシアニン色素のベンゼン環などの骨格に極性基
を導入した誘導体であるが、吸収波長がシフトしたり安
定性が悪くなったり、また導入できる極性基としてはス
ルホン基などに限定されているという問題点があった。PROBLEMS TO BE SOLVED BY THE INVENTION Polar group derivatives of cyanine dyes are mainly classified into two groups, one of which is N-
Although it is a derivative in which a carboxy group or a succinimide group is introduced at the alkyl terminal, its water solubility was not yet sufficient. The other is a derivative in which a polar group is introduced into the skeleton such as the benzene ring of a cyanine dye, but the absorption wavelength shifts or the stability deteriorates, and the polar group that can be introduced is limited to a sulfone group or the like. There was a problem that
【０００４】そこで、本発明の目的は、水に難溶である
シアニン色素を安定に水溶化することである。Therefore, an object of the present invention is to stably solubilize a poorly water-soluble cyanine dye in water.
【０００５】更に、該色素で蛋白質を標識した安定な色
素標識蛋白質を調製することである。Further, it is to prepare a stable dye-labeled protein in which the protein is labeled with the dye.
【０００６】上記目的は以下の本発明により達成され
る。The above object can be achieved by the present invention described below.
【０００７】即ち、本発明は、窒素原子を有するヘテロ
環を有する（メロ）シアニン色素において、該窒素原子
が炭素に結合し、該α炭素もしくは隣接する炭素主鎖に
カルボキシ基が結合していることを特徴とする蛋白質標
識用（メロ）シアニン色素、及び該色素のカルボキシ基
に蛋白質がペプチド結合していることを特徴とする色素
標識蛋白質である。That is, in the present invention, in a (mero) cyanine dye having a heterocycle having a nitrogen atom, the nitrogen atom is bonded to carbon, and the carboxy group is bonded to the α carbon or the adjacent carbon main chain. A (melo) cyanine dye for protein labeling, which is characterized by the above, and a dye-labeled protein characterized in that the protein is peptide-bonded to the carboxy group of the dye.
【０００８】シアニン色素を水溶化し、且つ極性基を誘
導する前と波長や安定性の変化が小さいためにはヘテロ
環の窒素原子に直接極性基を誘導するのが好ましい。It is preferable to introduce the polar group directly into the nitrogen atom of the heterocyclic ring in order to solubilize the cyanine dye and to reduce the change in wavelength and stability before the introduction of the polar group.
【０００９】本発明は窒素原子を含むシアニン色素にお
いて水溶性のアミノ酸を窒素原子に結合させたＮ−アミ
ノ酸シアニン色素としたことを特徴とする。The present invention is characterized in that the cyanine dye containing a nitrogen atom is an N-amino acid cyanine dye in which a water-soluble amino acid is bonded to the nitrogen atom.
【００１０】またこれらのＮ−アミノ酸シアニン色素で
標識した蛋白質に関する。It also relates to proteins labeled with these N-amino acid cyanine dyes.
【００１１】本発明のＮ−アミノ酸シアニン色素を構造
式で表すとThe N-amino acid cyanine dye of the present invention is represented by a structural formula.
【００１２】[0012]
【外１】 で表される。Ｒ1はアルキル基である。ｍは整数であ
る。Ｙ1およびＹ2は−ＣＨ2−、−ＣＭｅ2−、−ＣＨ＝
ＣＨ−、酸素原子（以下Ｏ）、硫黄原子（以下Ｓ）、セ
レン原子（以下Ｓｅ）、ＮＨのうち１つである。Ｙ3は
Ｍｅ、Ｅｔである。Ｚ1およびＺ2はクロル基、ニトロ
基、アミノ基、ベンゼン環などである。Ｒ9およびＲ12
はＨあるいはアミノ基あるいはアルキルアミノ基あるい
はアミノ基を有するアルキル基、Ｒ10およびＲ13はカル
ボキシル基、Ｒ11およびＲ14はＨあるいはアルキルであ
る。[Outer 1] It is represented by. R 1 is an alkyl group. m is an integer. Y 1 and Y 2 are -CH 2 -, - CMe 2 - , - CH =
It is one of CH-, an oxygen atom (hereinafter O), a sulfur atom (hereinafter S), a selenium atom (hereinafter Se), and NH. Y 3 is Me or Et. Z 1 and Z 2 are chloro group, nitro group, amino group, benzene ring and the like. R 9 and R 12
Is H or an amino group, an alkylamino group or an alkyl group having an amino group, R 10 and R 13 are carboxyl groups, and R 11 and R 14 are H or alkyl.
【００１３】上記構造式はシアニン色素の一般的な例で
あり、本発明は下記構造式のヘテロ環を持つことを特徴
とする。The above structural formulas are general examples of cyanine dyes, and the present invention is characterized by having a heterocycle represented by the following structural formula.
【００１４】[0014]
【外２】 [Outside 2]
【００１５】さらには該色素がペプチド結合で結合した
蛋白質で、一般的な構造式は以下で表されるものであ
る。Further, the dye is a protein bound by a peptide bond, and its general structural formula is as shown below.
【００１６】[0016]
【外３】 [Outside 3]
【００１７】本発明をさらに詳述する。The present invention will be described in more detail.
【００１８】本発明のシアニン色素とは複数のヘテロ環
がポリメチン鎖により結合されているもののうち、窒素
原子を含むものである。The cyanine dye of the present invention is one in which a plurality of heterocycles are bound by a polymethine chain and contains a nitrogen atom.
【００１９】より好ましくは長波長領域に吸収があり、
さらには蛍光物質であることが好ましい。More preferably, there is absorption in the long wavelength region,
Further, it is preferably a fluorescent substance.
【００２０】上述したように生体由来の物質が混入する
可能性がある場合にはこれと光学的に識別する必要があ
り、長波長領域（約６００ｎｍ以上）に吸収があること
が好ましい。一般にはシアニン色素の共役系を長くする
と長波長吸収となることが理論および実験から確かめら
れている。ヘテロ環のベンゼン環をナフタレン環に変え
ることによっても若干の長波長化が計れる。As described above, when there is a possibility that a substance derived from a living body is mixed, it is necessary to optically distinguish it from the substance, and it is preferable that there is absorption in the long wavelength region (about 600 nm or more). It is generally confirmed from theory and experiment that long-wave absorption occurs when the conjugated system of the cyanine dye is lengthened. A slightly longer wavelength can also be achieved by changing the benzene ring of the heterocycle to a naphthalene ring.
【００２１】アミノ酸型シアニン色素について詳述す
る。The amino acid type cyanine dye will be described in detail.
【００２２】シアニン色素の窒素原子が炭素原子に結合
し、該α位の炭素原子あるいは隣接炭素主鎖上の炭素
（例えばβ位やε位）にカルボキシル基が結合している
ことを特徴とする。The nitrogen atom of the cyanine dye is bonded to a carbon atom, and the carboxyl group is bonded to the carbon atom at the α-position or the carbon on the adjacent carbon main chain (for example, β-position or ε-position). .
【００２３】シアニン色素の窒素原子は分子全体の安定
性により３級（中性）と４級（カチオン）の両状態を取
りうる。よって上記構造によりアミノ酸類似の性質、す
なわち水のｐＨにたいする溶解度の変化がある。該アミ
ノ酸型シアニン色素の窒素原子が結合しているα位炭素
やその隣接主鎖の炭素にアミノ基を付加することにより
ペプチド結合をさらに伸ばすこともできる。The nitrogen atom of the cyanine dye can assume both a tertiary (neutral) and a quaternary (cation) state depending on the stability of the whole molecule. Therefore, due to the above structure, there is an amino acid-like property, that is, there is a change in solubility with respect to the pH of water. The peptide bond can be further extended by adding an amino group to the α-position carbon to which the nitrogen atom of the amino acid type cyanine dye is bonded or the carbon of the main chain adjacent thereto.
【００２４】これらアミノ酸型シアニンをペプチド結合
で蛋白質に結合させることを特徴とする。It is characterized in that these amino acid type cyanines are bound to proteins by peptide bonds.
【００２５】アミノ酸型シアニン色素による蛋白質の標
識の場合にはジシクロカルボジイミド（以下ＤＣＣ）な
どを用いて化学的にペプチド結合を形成するのが一般的
である。上述したようにペプチド結合可能なアミノ基を
持つ場合には、複数個のシアニンを結合させることも可
能である。In the case of labeling a protein with an amino acid type cyanine dye, it is common to chemically form a peptide bond using dicyclocarbodiimide (hereinafter referred to as DCC). When it has an amino group capable of forming a peptide bond as described above, it is possible to bond a plurality of cyanines.
【００２６】[0026]
実施例１．アミノ酸型シアニン色素の合成例 図１に示した反応スキーム（Ｆｒａｎｃｅｓ Ｍ．Ｈａ
ｍｅｒ著Ｔｈｅ Ｃｙａｎｉｎｅ Ｄｙｅｓ Ａｎｄ
Ｒｅｌａｔｅｄ Ｃｏｍ−ｐｏｕｎｄｓなど）に従って
合成した。１５．９ｇの２，２，３−Ｔｒｉｍｅｔｈｙ
ｌ−ｉｎｄｏｌｉｎ（ｍｗ．１５９．２３）を１５．６
ｇのＥｔｈｙｌ Ｉｏｄｉｄｅ（ｍｗ．１５５．９７）
に加え、７０℃で３時間加熱還流した。冷却しエーテル
を加えて析出した赤色結晶を濾過して少量の冷やしたイ
ソプロピルアルコールで洗浄後、エタノールで再結晶し
た（以下Ｅｔ体）。Example 1. Example of Synthesis of Amino Acid Type Cyanine Dye Reaction Scheme (Frances M. Ha
by The Mer The Cyanine Dyes And
Synthesized according to Related Com-pounds, etc.). 15.9g of 2,2,3-Trimethy
1-indolin (mw.159.23) to 15.6
g Ethyl Iodide (mw.155.97)
In addition, the mixture was heated under reflux at 70 ° C. for 3 hours. After cooling, ether was added and the precipitated red crystals were filtered, washed with a small amount of cooled isopropyl alcohol, and recrystallized with ethanol (hereinafter referred to as Et form).
【００２７】２−ブロモプロピオン酸（ｍｗ．１５２．
９８）１５．３ｇをアセトニトリル中でヨウ化ナトリウ
ムと２，３，３−Ｔｒｉｍｅｔｈｙｌ−ｉｎｄｏｌｉｎ
とともに７０℃で３時間加熱還流した。冷却してエーテ
ルを加え析出した赤色結晶を濾過して少量の冷やしたイ
ソプロピルアルコールで洗浄後、エタノールで再結晶し
た（以下Ａｍ体）。2-Bromopropionic acid (mw.152.
98) 15.3 g of 2,3,3-Trimethyl-indolin with sodium iodide in acetonitrile
It was refluxed with 70 ° C. for 3 hours. After cooling and adding ether, the precipitated red crystals were filtered, washed with a small amount of cooled isopropyl alcohol, and recrystallized with ethanol (hereinafter referred to as Am body).
【００２８】Ａｍ体３．３ｇをエタノール５０ｍｌに溶
解し、２．８ｇのグルタコンアルデヒドジアニル塩酸塩
を加えて１時間加熱還流した。Ｅｔ体３．１ｇを加え
て、１時間加熱還流し、さらにナトリウムエトキサイド
を加えて５分間加熱をつづけ、氷冷して少量の水で水
洗、エーテルで洗浄し、メタノールで再結晶した（アミ
ノ酸型シアニン色素の一般構造式において、Ｒ1＝Ｅ
ｔ、Ｒ9＝ＮＨ2、Ｒ10＝ＣＯＯＨ、Ｒ11＝ＣＨ3、Ｙ1＝
Ｙ2＝Ｃ（ＣＨ3）2、Ｙ3＝Ｈ、Ｚ1＝Ｚ2＝ｎｏｎｅ、Ｘ
＝Ｂｒ、ｎ＝３）。3.3 g of Am compound was dissolved in 50 ml of ethanol, 2.8 g of glutaconaldehyde dianyl hydrochloride was added, and the mixture was heated under reflux for 1 hour. 3.1 g of Et form was added and the mixture was heated under reflux for 1 hour, sodium ethoxide was further added and continued heating for 5 minutes, ice-cooled, washed with a small amount of water, washed with ether, and recrystallized from methanol (amino acid). In the general structural formula of the type cyanine dye, R 1 = E
t, R 9 = NH 2 , R 10 = COOH, R 11 = CH 3 , Y 1 =
Y 2 = C (CH 3 ) 2 , Y 3 = H, Z 1 = Z 2 = none, X
= Br, n = 3).
【００２９】このシアニン色素のｐＫａは２．３であっ
た。アルカリ性側のｐＫａは不明瞭であった。また、２
５℃のｐＨ７の水１ｍｌに２００ｍｇ以上溶解した。The pKa of this cyanine dye was 2.3. The pKa on the alkaline side was unclear. Also, 2
200 mg or more was dissolved in 1 ml of water having a pH of 7 at 5 ° C.
【００３０】この水溶液の吸収極大波長は７４０ｎｍ
で、キセノンランプで励起したところ７８０ｎｍの蛍光
を発した。ｐＫａ以下のｐＨにおける吸収極大波長は７
２０ｎｍ付近でプロトンの解離による影響があるものと
考えられる。The maximum absorption wavelength of this aqueous solution is 740 nm
When excited with a xenon lamp, it emitted fluorescence of 780 nm. The absorption maximum wavelength at pH below pKa is 7
It is considered that there is an influence of proton dissociation near 20 nm.
【００３１】実施例２．アミノ酸型シアニン色素の変形
例 実施例１においてＡｍ体２当量にたいしてグルタコンア
ルデヒドジアニリルを１当量の割合で反応させるとＮ、
Ｎ′−ジアラニルシアニン色素が合成できた。このシア
ニン色素は２５℃のｐＨ７の水１ｍｌに２００ｍｇ以上
溶解し実施例１より水溶性が高かった（アミノ酸型シア
ニン色素の一般構造式において、Ｒ1＝Ｅｔ、Ｒ9＝Ｒ12
＝ＮＨ2、Ｒ10＝Ｒ13＝ＣＯＯＨ、Ｒ11＝Ｒ14＝ＣＨ3、
Ｙ1＝Ｙ2＝Ｃ（ＣＨ3）2、Ｙ3＝Ｈ、Ｚ1＝Ｚ2＝ｎｏｎ
ｅ、Ｘ＝Ｂｒ、ｎ＝３）。Example 2. Deformation of amino acid type cyanine dye
In Example 1, when 2 equivalents of Am isomer were reacted with 1 equivalent of glutaconaldehyde dianilyl, N,
An N'-dialanyl cyanine dye could be synthesized. This cyanine dye was dissolved in 200 ml or more in 1 ml of water having a pH of 7 at 25 ° C. and had higher water solubility than that of Example 1 (in the general structural formula of the amino acid type cyanine dye, R 1 = Et, R 9 = R 12).
= NH 2 , R 10 = R 13 = COOH, R 11 = R 14 = CH 3 ,
Y 1 = Y 2 = C (CH 3 ) 2 , Y 3 = H, Z 1 = Z 2 = non
e, X = Br, n = 3).
【００３２】このシアニン色素のｐＫａは２．３であっ
た。アルカリ性側のｐＫａは不明瞭であった。水溶液の
光学的特徴は実施例１と同様であった。The pKa of this cyanine dye was 2.3. The pKa on the alkaline side was unclear. The optical characteristics of the aqueous solution were the same as in Example 1.
【００３３】実施例３．アミノ酸型シアニン色素により
色素標識した蛋白質 実施例１のアミノ酸型シアニン色素により蛋白質を色素
標識した。Example 3. By amino acid type cyanine dye
Dye-Labeled Protein The protein was dye-labeled with the amino acid type cyanine dye of Example 1.
【００３４】Ｃ末端を保護した蛋白質と実施例１で合成
したアミノ酸型シアニン色素とをＤＣＣ存在下で縮合反
応を行なった。蛋白質に標識しても実施例１と同様の光
学的性質を示した。The C-terminal protected protein and the amino acid type cyanine dye synthesized in Example 1 were subjected to a condensation reaction in the presence of DCC. Even when the protein was labeled, it showed the same optical properties as in Example 1.
【００３５】また実施例２のアミノ酸型シアニン色素を
用いても同様の光学的性質であった。The same optical properties were obtained even when the amino acid type cyanine dye of Example 2 was used.
【００３６】[0036]
１．シアニン色素を水溶化できる。 ２．蛋白質をシアニン色素で標識しても水溶性は変化し
ない。 ３．水溶化したシアニン色素を標識した蛋白質はシアニ
ン色素としての光学的な性質および蛋白質としての性質
（酸素との反応性など）を併せ持つことができる。1. The cyanine dye can be made water soluble. 2. Labeling the protein with a cyanine dye does not change its water solubility. 3. A protein labeled with a water-solubilized cyanine dye can have both optical properties as a cyanine dye and properties as a protein (reactivity with oxygen, etc.).
【図１】本発明の蛋白質標識用シアニン色素の合成スキ
ームの一例。FIG. 1 shows an example of a synthetic scheme of a cyanine dye for protein labeling of the present invention.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.5 識別記号 庁内整理番号 ＦＩ 技術表示箇所 Ｇ０１Ｎ 33/68 7055−2Ｊ (72)発明者 川口 正浩 東京都大田区下丸子３丁目30番２号キヤノ ン株式会社内─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. 5 Identification number Reference number within the agency FI Technical indication location G01N 33/68 7055-2J (72) Inventor Masahiro Kawaguchi 3-30-2 Shimomaruko, Ota-ku, Tokyo Canon Inc.
Claims (2)
ロ）シアニン色素において、該窒素原子が炭素に結合
し、該α炭素もしくは隣接する炭素主鎖にカルボキシ基
が結合していることを特徴とする蛋白質標識用（メロ）
シアニン色素。1. A (mero) cyanine dye having a heterocycle having a nitrogen atom, wherein the nitrogen atom is bonded to carbon, and a carboxy group is bonded to the α carbon or an adjacent carbon main chain. For protein labeling (Mello)
Cyanine dye.
アニン色素のカルボキシ基に蛋白質がペプチド結合して
いることを特徴とする色素標識蛋白質。2. A dye-labeled protein, wherein the protein is peptide-bonded to the carboxy group of the (mero) cyanine dye for protein labeling according to claim 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4272916A JPH06123740A (en) | 1992-10-12 | 1992-10-12 | @(3754/24)mero) cyanine pigment for pprotein-labeling and pigment-labelled protein |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4272916A JPH06123740A (en) | 1992-10-12 | 1992-10-12 | @(3754/24)mero) cyanine pigment for pprotein-labeling and pigment-labelled protein |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH06123740A true JPH06123740A (en) | 1994-05-06 |
Family
ID=17520545
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP4272916A Pending JPH06123740A (en) | 1992-10-12 | 1992-10-12 | @(3754/24)mero) cyanine pigment for pprotein-labeling and pigment-labelled protein |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH06123740A (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5616502A (en) * | 1995-05-19 | 1997-04-01 | Molecular Probes, Inc. | Non-specific protein staining using merocyanine dyes |
| JP2004510011A (en) * | 2000-09-19 | 2004-04-02 | リ−コール インコーポレーティッド | Cyanine dye |
| JP2007016038A (en) * | 1996-07-26 | 2007-01-25 | Nen Life Science Products Inc | Compound and method for synthesizing sulfoindocyanine dye |
| JP2009526212A (en) * | 2006-02-10 | 2009-07-16 | アジレント・テクノロジーズ・インク | Protein analysis method and kit using polymethine marker dye |
| US8865904B2 (en) | 2005-05-11 | 2014-10-21 | Life Technologies Corporation | Fluorescent chemical compounds having high selectivity for double stranded DNA, and methods for their use |
| US9040561B2 (en) | 2003-12-05 | 2015-05-26 | Life Technologies Corporation | Methine-substituted cyanine dye compounds |
| CN116239893A (en) * | 2023-03-21 | 2023-06-09 | 大连理工大学 | Quaternary ammonium salt modified cyanine fluorescent dye and its synthesis and application |
-
1992
- 1992-10-12 JP JP4272916A patent/JPH06123740A/en active Pending
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5616502A (en) * | 1995-05-19 | 1997-04-01 | Molecular Probes, Inc. | Non-specific protein staining using merocyanine dyes |
| JP2008096437A (en) * | 1995-05-19 | 2008-04-24 | Molecular Probes Inc | Merocyanine dye protein stain |
| JP2007016038A (en) * | 1996-07-26 | 2007-01-25 | Nen Life Science Products Inc | Compound and method for synthesizing sulfoindocyanine dye |
| JP2004510011A (en) * | 2000-09-19 | 2004-04-02 | リ−コール インコーポレーティッド | Cyanine dye |
| US9040561B2 (en) | 2003-12-05 | 2015-05-26 | Life Technologies Corporation | Methine-substituted cyanine dye compounds |
| US9403985B2 (en) | 2003-12-05 | 2016-08-02 | Life Technologies Corporation | Methine-substituted cyanine dye compounds |
| US10005908B2 (en) | 2003-12-05 | 2018-06-26 | Life Technologies Corporation | Methine-substituted cyanine dye compounds |
| US8865904B2 (en) | 2005-05-11 | 2014-10-21 | Life Technologies Corporation | Fluorescent chemical compounds having high selectivity for double stranded DNA, and methods for their use |
| US9115397B2 (en) | 2005-05-11 | 2015-08-25 | Life Technologies Corporation | Fluorescent chemical compounds having high selectivity for double stranded DNA, and methods for their use |
| US9366676B2 (en) | 2005-05-11 | 2016-06-14 | Life Technologies Corporation | Fluorescent chemical compounds having high selectivity for double stranded DNA, and methods for their use |
| JP2009526212A (en) * | 2006-02-10 | 2009-07-16 | アジレント・テクノロジーズ・インク | Protein analysis method and kit using polymethine marker dye |
| US9297807B2 (en) | 2006-02-10 | 2016-03-29 | Agilent Technologies, Inc. | Protein analysis using a polymethine marker dye |
| CN116239893A (en) * | 2023-03-21 | 2023-06-09 | 大连理工大学 | Quaternary ammonium salt modified cyanine fluorescent dye and its synthesis and application |
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