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Glutathione-responsive disulfide-bond dicyanine dye as well as preparation method and application thereof

A disulfide bond, dicyanine technology, applied in organic dyes, chemical instruments and methods, methine-based/polymethine-based dyes, etc., can solve the problems of poor imaging resolution of tumor sites, and achieve easy preparation, good stability, good targeting effect

Active Publication Date: 2019-09-27
PEKING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The purpose of the present invention is to overcome the disadvantages of poor imaging resolution of tumor sites by existing fluorescent probes, and to provide a glutathione-responsive disulfide-bonded biscyanine dye and a preparation method thereof

Method used

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  • Glutathione-responsive disulfide-bond dicyanine dye as well as preparation method and application thereof
  • Glutathione-responsive disulfide-bond dicyanine dye as well as preparation method and application thereof
  • Glutathione-responsive disulfide-bond dicyanine dye as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] R in this example 1 is a sulfonic acid group, R 2 Be 4-sulfonic acid butyl, X is the preparation of the bisindole compound C1 of NH, synthetic method is as follows:

[0039]

[0040] Add carboxyindole compound A1 (100mg), TSTU (2-succinimidyl-1,1,3,3-tetramethyluronium tetrafluoroborate) (104mg) and DIPEA (N,N-diiso Propylethylamine) (114 mg) was mixed at room temperature, and after stirring for 3 hours, cystamine dihydrochloride (43 mg) was added, and after stirring for 16 hours, the solvent was spin-dried, and bisindole was obtained by reverse-phase silica gel column chromatography. Compound C1, yield 81%.

[0041] After detection, the product C 36 h 51 N 4 o 8 S 4 + The structure is correct.

[0042] MS(MALDI-TOF): theoretical value [M+H] + =795.26, experimental value [M+H] + =795.30.

[0043] 1 H NMR (400MHz,D 2 O)δ7.96–7.76(m,2H),7.76–7.52(m,2H),6.55(d,J=8.5Hz,2H),3.69–3.52(m,4H),3.44–3.31(m,2H ),3.23–3.14(m,2H),3.15–3.03(m,4H),2.96–2.81(m,4H),1.7...

Embodiment 2

[0045] R in this example 1 is a sulfonic acid group, R 2 Be 4-sulfonic acid butyl, n=2, X is the preparation of the formula I compound of NH, and synthetic method is as follows:

[0046]

[0047] Effect of bisindole C1 (15mg) and hydrochloric acid-N-(3-phenylamino-2-propenylidene)aniline (9.27mg) in acetic acid-acetic anhydride mixed solvent (acetic acid:acetic anhydride=0.5mL:0.5mL) Reaction at 50~140°C for 2 hours to obtain the semicyanine intermediate, rotary evaporation to remove the solvent, adding indole compound D1 (15.6mg), under the action of acetic acid-pyridine mixed solvent (acetic acid:pyridine=1mL:1mL) under the action of 80 ℃ for 2 hours, add diethyl ether to precipitate to obtain the crude product, and obtain the pure compound of formula I through column chromatography, the yield is 63%

[0048] After detection, the product C 72 h 92 N 6 o 2 0S 8 The structure is correct.

[0049] MS(MALDI-TOF): theoretical value [M+H] + =1617.41, experimental value...

Embodiment 3

[0052] This example is R 1 is a sulfonic acid group, R 2 Be 4-sulfonic acid butyl, X is the preparation of the formula III compound of NH, synthetic method is as follows:

[0053]

[0054] Using water as a solvent, add dye J1 (200mg) and cystamine dihydrochloride (22.2mg) containing active groups, react at 50°C for 12 hours, remove the solvent by rotary evaporation, and obtain the residue by column chromatography Pure compound of formula III, yield 72%.

[0055] After detection, the product C 40 h 53 N 3 o 12 S 5 The structure is correct.

[0056] MS(MALDI-TOF): theoretical value [M 1 / 2 +H] + =928.22, experimental value [M 1 / 2 +H] + =928.29.

[0057] 1 H NMR (500MHz,D 2 O)δ7.86–7.57(m,12H),7.15–6.92(m,4H),5.84–5.64(m,4H),4.15–3.93(m,4H),3.50(s,5H),3.00–2.88 (m,5H),2.88–2.73(m,8H),2.49–2.28(m,8H),1.81–1.61(m,22H),1.57(s,24H).

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Abstract

The invention discloses glutathione-responsive disulfide-bond dicyanine dye as well as a preparation method and application thereof. The prepared disulfide-bond dicyanine dye contains a disulfide bond fractured in response to glutathione; double dye fluorescence is quenched due to aggregation before response, and is recovered after response. Since the concentration of the glutathione in tumor cells is much higher than that in normal cells, the dye can realize fluorescence imaging with higher resolutionof tumor locations, and the problem that the imaging resolution for the tumor locations of existing cyanine dye is poor is solved. In addition, the disulfide-bond dicyanine dye prepared by the method dislcosed by the invention is good in stability and low in toxicity, and can be applied to molecular fluorescence imaging and photodynamic and sonodynamic therapy of tumors. Furthermore, the dye is short in synthetic route, high in yield, easy to operate, and suitable for industrialized production.

Description

technical field [0001] The invention belongs to the field of biomedical materials, and in particular relates to a glutathione-responsive disulfide bonded biscyanine dye, a preparation method and application thereof. Background technique [0002] Molecular imaging technology can be used for pathological monitoring and diagnosis of tumor cells at the molecular level, and can also be used for minimally invasive treatment of tumor tissues. The key to this technology lies in the molecular probe, the performance of the molecular probe directly determines the success or failure of the molecular imaging technology. Cyanine dye-based molecular probes are widely used in molecular imaging technology because of their wide absorption wavelength range (500-850nm), high biocompatibility, and strong cell membrane penetration performance. [0003] General cyanine dyes, such as FDA-approved indocyanine green (ICG), do not have tumor cell targeting, and the resolution of fluorescence imaging ...

Claims

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Application Information

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IPC IPC(8): C09B23/10C07D209/08A61K41/00A61K49/00A61P35/00
CPCA61K41/0033A61K41/0057A61K49/0034A61P35/00C07D209/08C09B23/10C09B23/107
Inventor 戴志飞莫善雁
Owner PEKING UNIV
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