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Amino acid-fluorophore compound and application thereof

A compound and fluorophore technology, applied in the field of medicine, can solve problems such as high cost, long test time, and low sensitivity

Active Publication Date: 2014-06-18
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, the screening of aminopeptidase N inhibitors is still based on the ultraviolet absorption method, which has the disadvantages of low sensitivity, high cost, and long testing time.

Method used

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  • Amino acid-fluorophore compound and application thereof
  • Amino acid-fluorophore compound and application thereof
  • Amino acid-fluorophore compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0022] Example 1: Preparation of 2-amino-4methylthio-N-(4-(2-oxo-2hydro-chromen-7-yloxy)phenyl)butanamide hydrochloride【L3】

[0023] Synthetic route 1

[0024]

[0025] Preparation of Intermediate 1:

[0026] Dissolve 14.9g of methionine in 110mL of 1M sodium hydroxide solution, place in an ice bath, slowly add 50mL of anhydrous THF solution containing 21.18g of di-tert-butyl carbonate dropwise, and at the same time use 1M sodium hydroxide solution to control the pH of the reaction solution at about 9, The dropwise addition was completed in about 1 hour, stirred for 1 hour in an ice bath, then removed from the ice bath, and stirred at room temperature for 15 hours. During the whole process, the pH of the system was kept at around 9. After the reaction was completed, THF was distilled off, washed with petroleum ether (100mL×3), the aqueous phase was adjusted to pH 2-3 with saturated citric acid solution, and extracted with ethyl acetate (100mL×3). Dry over magnesium sulfa...

example 2

[0040]Example 2: Preparation of 2-amino-N-(2-((2-oxo-2hydro-chromen-7-yloxy)-methyl)phenyl)pentanamide hydrochloride【L38】

[0041] Synthetic route 2

[0042]

[0043] Preparation of Intermediate 7:

[0044] Dissolve 1.2g Boc-L-norvaline in 50mL dichloromethane, add 0.75g HOBT, 1.05g EDCI, stir at room temperature for 15min, add 0.62g o-aminobenzyl alcohol, and stir at room temperature for 10 hours. The reaction solution was washed with saturated citric acid (50 mL×3), saturated sodium bicarbonate (50 mL×3), and saturated brine (50 mL×1). Dry over anhydrous magnesium sulfate overnight. Concentrate and recrystallize from ethyl acetate-n-hexane to obtain 0.97 g of a white solid with a yield of 60% and a melting point of 110.0-122.3°C.

[0045] Preparation of intermediate 8:

[0046] Using Intermediate 7 as raw material, according to the preparation method of Intermediate 5, Intermediate 8 was obtained as a brown oil with a yield of 80%.

[0047] Preparation of intermedia...

example 3

[0052] Example 3: 2-amino-N-(2-((2-oxo-2hydro-chromen-7-yloxy)-methyl)pyridin-3-yl)propionamide hydrochloride [L55 】Preparation

[0053] Synthetic route 3

[0054]

[0055] References for the synthesis of intermediates 10 and 11 [(a) Beyermann, M.; Bienert, M.; Niedrich, H; Carpino, L.A.; Sadat-Aalaee, D. Rapid continuous peptide synthesis via FMOC amino acid chloride coupling and4-( aminomethyl)piperidine deblocking.J Org Chem,1990,55,721-728.(b)Carpino,L A.; Xia,J.S.;El-Faham,A.3-Hydroxy-4-oxo-3,4-dihydro-5- azabenzo-1,2,3-triazene. J Org Chem, 2004, 69, 54-61.].

[0056] Preparation of Intermediate 12:

[0057] Dissolve 2.67g of intermediate 11 and 3mL of pyridine in 50mL of dioxane, add 0.63g of intermediate 10, reflux for 1 hour and cool to room temperature. Concentrate, dissolve with 200mL ethyl acetate, wash with saturated sodium bicarbonate (50mL×3), and saturated brine (50mL×1). Dry over anhydrous magnesium sulfate overnight. Concentrate and recrystallize fro...

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Abstract

The invention relates to an amino acid-fluorophore compound and application of the compound, wherein the general structural formula of the amino acid-fluorophore compound is (I), (II), (III), and (IV) or a free form thereof, wherein R1 is selected from various amino acid side chains, preferably methyl, propyl, 2-methylthio ethyl, benzyl, phenylethyl, 2-cyclohexyl ethyl, 4-isopropyl phenyl and 4-dimethyl amino phenyl; R2 is selected from various fluorophores, preferably 7-hydroxyl coumarin, naphthalimide fluorophores, Nile red series and Cy fluorophores; and X is C or N. Fluorescent probe molecules can be used for detecting the activity (enzyme level and cell level) of aminopeptidase N, can be used as a probe tool for detecting the tissue distribution of aminopeptidase N and tumor tissue imaging, and can be used as a diagnosis tool for various diseases due to abnormal expression of aminopeptidase N. In addition, the preparation method of the compound has the advantages of mild reaction conditions, easily-accessible and cheap raw materials and simplicity in operation and after-treatment.

Description

technical field [0001] The invention relates to an amino acid-linker-fluorophore compound and its application as a small-molecule fluorescent probe of aminopeptidase N and in screening aminopeptidase N inhibitors, belonging to the technical field of medicines. Background technique [0002] Aminopeptidase N (A PN, CD13) is widely expressed on the surface of kidney and intestinal brush border cells, bone marrow progenitor cell membranes, monocyte membranes, central nervous system synaptic cell membranes, fibroblasts, endothelial cell membranes, and placental cell membranes. Degradation of the N-terminus releases amino acids. Compared with normal cell activity, this enzyme is overexpressed on the surface of tumor cells and plays an important role in tumor invasion and angiogenesis. In addition, the protease, as a receptor of many viruses (such as disseminated gastroenteritis virus that causes acute gastroenteritis in neonatal pigs and coronavirus HCV229E that causes human uppe...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D311/16C07D221/14C07D265/34C07D209/12C07D213/75C07D401/12C07D413/12C07D401/14C07D405/12C09K11/06C12Q1/34C12Q1/02
Inventor 李敏勇杜吕佩陈来中
Owner SHANDONG UNIV
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