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Ortho-dithiol reactive treatment probe for drug release monitoring and preparation method of ortho-dithiol reactive treatment probe

A dithiol and reactive technology, applied in the field of reactive therapeutic probe compounds, can solve problems such as difficult to locate the exact position of the drug, achieve good cell membrane permeability, improve tissue penetration depth, and fast response

Active Publication Date: 2021-07-27
UNIV OF JINAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In such a system, the fluorophore can report whether the drug is released, but it is difficult to pinpoint the exact location of the drug

Method used

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  • Ortho-dithiol reactive treatment probe for drug release monitoring and preparation method of ortho-dithiol reactive treatment probe
  • Ortho-dithiol reactive treatment probe for drug release monitoring and preparation method of ortho-dithiol reactive treatment probe
  • Ortho-dithiol reactive treatment probe for drug release monitoring and preparation method of ortho-dithiol reactive treatment probe

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] A method for preparing an o-dithiol-responsive therapeutic probe for drug release monitoring, the steps comprising:

[0027] 1) Synthesis of compound 1:

[0028] 4-Aminophenylarsenic oxide (0.29 g, 1.6 mmol) was dissolved in absolute ethanol (20 mL), then 2,3-dimercapto-1-propanol (0.24 g, 1.9 mmol) was added to the solution , the reaction mixture was refluxed for 3 hours, and when the color of the reactant became transparent, the solvent was evaporated under reduced pressure, and column purification (petroleum ether / acetone=5 / 1) gave Compound 1 with a yield of 70%.

[0029] Synthesis of compound 2:

[0030] N-Boc-3-alanine (0.18 g, 0.96 mmol), HATU (0.45 g, 1.2 mmol) and DIPEA (208 μg, 1.2 mmol) were dissolved in anhydrous DMF solution (20 mL), and the reaction system was Stir at room temperature for 0.5-1 hour, then add compound 1 (0.23 g, 0.8 mmol), stir the solution at room temperature for 12 hours, pour into about 800 mL of water, and extract the aqueous phase wi...

Embodiment 2

[0044] Spectral properties of probe CP-VD and its fluorescence response to o-dithiol

[0045] Take the CP-VD synthesized in Example 1 in a test tube, mix it with 4 mL phosphate buffer (pH 4.5) to prepare the probe stock solution (10 μM), then add o-dithiol, and use phosphate buffer to dissolve the final The volume was adjusted to 5 mL. Both absorption and fluorescence spectra were measured in phosphate buffered saline at 37°C. Samples were measured in 1 cm x 1 cm quartz cuvettes (3 mL volume). Absorption measurements were recorded on a UV-Vis spectrometer and fluorescence studies were performed on a fluorescence spectrophotometer with an excitation wavelength of 405 nm, a slit width of 5 nm for both excitation and emission, and a photomultiplier tube detector voltage of 600 V. The free probe CP-VD (10 μM) had an absorbance maximum close to 400 nm and had negligible fluorescence intensity at 37 °C, but upon addition of rBSA (which donates o-dithiol), the maximum absorbance wa...

Embodiment 3

[0047] Specific detection of o-dithiol by probe CP-VD

[0048] Take the CP-VD stock solution (10 μM) in Example 2, after adding the donor of o-dithiol, including reduced human serum albumin (rHSA), rBSA, reduced thioredoxin reductase and thiox The fluorescence of the reduced protein and the probe was significantly enhanced. In contrast, reducing agents, such as dithiothreitol (DTT), low molecular weight proteins, such as cysteine ​​(Cys), homocysteine ​​(Hcy) and glutathione (GSH) and without The proteins with ortho-dithiols had negligible responses to the probe, proving that the fluorescent signal of the probe was caused by the ortho-dithiols.

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Abstract

The invention discloses an ortho-dithiol reactive treatment probe for drug release monitoring and a preparation method of the ortho-dithiol reactive treatment probe. The structure of a probe compound is shown as a formula I in the specification. A probe molecule is composed of three main parts, namely fluorescent camptothecin (CPT), a self-cleavable connecting fragment and a specific ortho-dithiol recognition group. When ortho-dithiol exists, amido bonds in the probe are cracked, then 1,6-sites in molecules are eliminated, so release of the active anticancer drug, namely the CPT is triggered, and the fluorescence of CPT is recovered. The probe has the advantages that the anticancer drug CPT can be used as a drug and can also be used as a fluorescence reporter, and drug distribution can be accurately tracked. Meanwhile, the probe can realize selective chemical detection of ortho-dithiol and monitoring of release of the anti-cancer drug at the same time.

Description

technical field [0001] The present invention relates to a reactive therapeutic probe compound for drug release monitoring, more specifically a fluorescent probe that releases anticancer drugs after being activated by o-dithiol and uses fluorescence imaging technology to monitor the drug release process. The needle compound and its preparation belong to the field of pharmaceutical analytical chemistry. Background technique [0002] Ortho-dithiol-containing proteins (VDPs) contain a pair of cysteine ​​thiols that are closely spaced in the three-dimensional structure of the protein and are usually actively involved in reversible dithiol / disulfide transitions. The exchange of dithiol / disulfide bonds within proteins is crucial to regulate the functions of a variety of proteins, such as redox-regulated enzymes, metabolic enzymes, transcription factors, and various receptors, etc. In addition to its special role as a redox center, protein ortho-dithiols are also key linking center...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/80C09K11/06A61K31/4745A61K49/00A61P35/00
CPCC07F9/80C09K11/06A61K31/4745A61K49/0019A61K49/0052A61P35/00C09K2211/1048C09K2211/1096
Inventor 颜梅卫先哲张晶杨小凤朱彤李成芳于京华
Owner UNIV OF JINAN
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