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Tyrosinase-activated double-quenching diagnosis and treatment prodrug and preparation thereof

A tyrosinase and quenching technology, which is applied in the field of double-quenched fluorescence diagnostic prodrug compounds, can solve the problems of low fluorescence masking efficiency and incomplete transfer, and achieve high drug loading, high activity and high response rate Effect

Active Publication Date: 2021-02-09
UNIV OF JINAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, single-fluorescent quenchers with fluorescence-canceling effects usually depend on the type of fluorophore, leading to either inefficient fluorescence masking or an incomplete shift of the equilibrium to the blocked lactone form, thus, most probes exhibit only a moderate degree of Fluorescence On Response

Method used

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  • Tyrosinase-activated double-quenching diagnosis and treatment prodrug and preparation thereof
  • Tyrosinase-activated double-quenching diagnosis and treatment prodrug and preparation thereof
  • Tyrosinase-activated double-quenching diagnosis and treatment prodrug and preparation thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0026] A method for preparing a tyrosinase-activated double-quenching prodrug for diagnosis and treatment, the steps comprising:

[0027] 1) Synthesis of Compound 1:

[0028] To prepare compound A from phthalic anhydride and 3-diethylaminophenol, compound A (3.15 g, 10 mmol) and 2,4-dihydroxybenzaldehyde (2 g, 12 mmol) were dissolved in trifluoroacetic acid solution (25 mL), stirred at 80°C for 18 hours, poured the cooled mixture into 25 mL of ice water, and washed with saturated Na 2 CO 3 The aqueous solution was neutralized to a pH of 7.5, the solvent was evaporated under reduced pressure, and column purification (dichloromethane / ethanol=20 / 1) gave compound 1 as a red powder with a yield of 50%.

[0029] Synthesis of Compound 2:

[0030] Compound 1 (0.75 g, 1.8 mmol), methyl 3-(bromomethyl)benzoate (0.62 g, 2.7 mmol) and Cs 2 CO 3 (1.05 g, 3.24 mmol) was dissolved in DMF solution (15 mL), stirred at 75 °C for 15 hours, after cooling to room temperature, 25 mL of water w...

Embodiment 2

[0038] In Vitro Detection Method of Reaction of Prodrug Molecule lyso-MT with Tyrosinase

[0039]In a test tube, take the prodrug molecule lyso-MT (50 μM) synthesized in Example 1 and mix thoroughly in 4 mL phosphate buffer saline and DMSO to prepare a stock solution, then add tyrosinase solution, and phosphate buffer saline The volume was adjusted to 5 mL. After reacting at 37°C for 30 minutes in the incubator, transfer 3 mL of the reaction solution to a 1 cm quartz cell, and ex / em Fluorescence is measured at wavelengths = 470 / 528nm. At the same time, a solution without adding tyrosinase was prepared as a control, and compared under the same conditions.

Embodiment 3

[0041] Fluorescent response of prodrug molecule lyso-MT to tyrosinase

[0042] Taking the prodrug compound solution (10 μM) in Example 2, after adding tyrosinase, it was observed that the fluorescence at about 528 nm increased by about 55 times, and the fluorescence quantum yield increased from less than 0.01 to 0.14. lyso-MT exhibited a good linear fluorescence response to tyrosinase in the concentration range from 0.5 to 60 U / mL, and the detection limit was determined to be 0.7 U / L, indicating that the prodrug has a sensitive and rapid response to tyrosinase .

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Abstract

The invention discloses a tyrosinase-activated double-quenching diagnosis and treatment prodrug and a preparation method thereof. The structure of a compound of the diagnosis and treatment prodrug isshown as a formula I. According to prodrug molecules, tyrosinase activated 3-hydroxy benzyloxy and an anti-cancer drug melphalan are simultaneously introduced as fluorescence quenching groups to reduce background fluorescence, and double quenching groups are self-eliminated by utilizing the hydroxylation effect of enzyme to form lactam, so that not only is the fluorophore activated, but also the active melphalan is released for cancer treatment. The prodrug has the advantages that: the dual-quenching fluorescent prodrug reduces background fluorescence, has quick-opening fluorescence response,and after being modified by a prodrug lysosome targeting group, the prodrug is successfully applied to tracking of drug release in vivo and targeting treatment of a tumor mouse model with abnormal enzyme activity expression.

Description

technical field [0001] The present invention relates to an enzyme-activated double-quenched fluorescent diagnostic prodrug compound in tumor cells, more specifically a double-quenched anti-cancer drug melphalan released after targeting lysosomes activated by tyrosinase Fluorescent prodrug molecules, and the use of fluorescent imaging to track drug release and prodrug compounds and preparations for tumor diagnosis and treatment, belong to the field of pharmaceutical analytical chemistry. Background technique [0002] Cancer is the most common life-threatening disease in the world. Although a variety of cancer treatment methods have been developed, there are still insufficient researches on how to improve the effectiveness of treatment and reduce side effects. Usually, one of the main causes of death from cancer is the metastasis of tumors, cancer cells are produced by the genetic differentiation of normal cells, which allows cancer cells to migrate and invade adjacent tissues...

Claims

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Application Information

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IPC IPC(8): C07D491/107A61K31/198A61K31/5377A61K47/54A61K49/00A61P35/00C09K11/06
CPCA61K31/198A61K31/5377A61K49/0041A61K49/0052A61K47/558A61P35/00C07D491/107C09K11/06C09K2211/1033
Inventor 颜梅卫先哲张晶魏全勇郝梦娇王妍马云飞
Owner UNIV OF JINAN
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