Environment-sensitive alpha1-adrenergic receptor near infrared fluorescence ligands and application thereof

An adrenaline and environment-sensitive technology, applied in the direction of fluorescence/phosphorescence, preparations for in vivo tests, luminescent materials, etc., can solve the problems of few applications and no selectivity of this coloring, so as to improve the signal-to-noise ratio and provide Sensitivity, effects of avoiding washing steps

Active Publication Date: 2015-11-18
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, its application in cellular fluorescence imaging of proteins is less
In initial research, it was found that Cy5 fluorescent ...

Method used

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  • Environment-sensitive alpha1-adrenergic receptor near infrared fluorescence ligands and application thereof
  • Environment-sensitive alpha1-adrenergic receptor near infrared fluorescence ligands and application thereof
  • Environment-sensitive alpha1-adrenergic receptor near infrared fluorescence ligands and application thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0030] Example 1: Synthesis of PTC-1~3

[0031]

[0032] Reagents and conditions: (a) 3-iodopropionic acid, acetonitrile, reflux, 48h, 81%; (b) methyl iodide, acetonitrile, reflux, 12h, 86%; (c) hydrochloric acid-N-(3-benzene Amino-2-propenylidene)aniline, AcOH / AC 2 O, 120℃, 4h; Pyridine / AcOH, 120℃, 4h; 30% two steps; (d) propargylamine, EDCI, DMAP, dichloromethane, r.t., 6h, 53%; (e) piperazine, H 2 O, 100°C, 81%; (f) acid chloride, TEA, acetonitrile, 1h, 0°C, 62-75%; (g) NaN 3 , DMSO, 100℃, 6h, 35-88%; (h) CuSO4, sodium ascorbate, tBuOH / H 2 O=2:1, 50°C, 1h, 48.9-67.3%.

[0033] Intermediate C3: 1-(2-carboxyethyl)-2,3,3-trimethyl-3H-indole-1-iodonium

[0034] 2,3,3-Trimethyl-3H-indole (1.0g, 6.23mmol) and 3-iodopropionic acid (1.86g, 9.3mmol) were dissolved in 15mL of acetonitrile, refluxed for 48 hours, and cooled to room temperature. After the solvent was spin-dried, 100 mL of ethyl acetate was slowly added under ultrasonic vibration, and a large amount of precipita...

example 2

[0061] Example 2: Synthesis of PTC-4~6

[0062]

[0063] Reagents and conditions: (a) H 2 O / acetonitrile,NaN 3 , 80℃, 20h, 43-74%; (b) TsCl, triethylamine, chloroform, r.t., 24h, 65-88%; (c) K 2 CO 3 , acetonitrile, 90°C, 64-69%; (d) CuSO4, sodium ascorbate, tBuOH / H 2 O=2:1, 50°C, 1h, 55.2-72.5%.

[0064] Intermediate 11a: 2-Azidoethanol

[0065] NaN 3 (3.12g, 48mmol) was carefully added to a mixed solution of 2-bromoethanol (2g, 16mmol) in acetonitrile (10mL) and water (40mL), stirred vigorously at 80°C for 20h, then cooled to room temperature. The reaction solution was extracted with dichloromethane (3×50 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off to obtain 0.7 g of a transparent oil with a yield of 50%. 1 HNMR (300MHz, CDCl3): δ3.80 (td, 2H, J 1 =4.8Hz,J 2 = 3.0Hz), 3.27(t, 2H, J = 5.4Hz), 1.96(s, 1H).

[0066] Intermediate 11b: 3-Azido-1-propanol

[0067] Synthesis of intermediate 11b Using 3-bromo-1-propanol as r...

example 3

[0088] Example three: the synthesis of PHC-1~3

[0089]

[0090] Reagents and conditions: (a) K 2 CO 3 , acetonitrile, 90°C, 73-96%; (b) CuSO4, sodium ascorbate, tBuOH / H 2 O=2:1, 50°C, 1h, 49.4-57.7%.

[0091] Intermediate PH1: 1-(2-azidoethyl)-4-(2-methoxyphenyl)piperazine

[0092] To the acetonitrile solution (30 mL) of 1-(2-methoxyphenyl)piperazine (665 mg, 3.46 mmol) and 11a (918 mg, 3.8 mmol) was added 1.43 g of potassium carbonate, and the mixture was refluxed for 24 h, then filtered immediately to obtain the filtrate. The solvent was evaporated and purified by silica gel column chromatography to obtain 690 mg of yellow oil with a yield of 76%. 1 HNMR (300MHz, CDCl 3 ): δ7.02-6.84(m,4H), 3.80(s,3H), 3.41(t,2H, J=6.0Hz), 3.11(m,4H), 2.73-2.65(m,6H); ESI- MS:m / z[M+H] + calcdforC 13 h 20 N 5 o + 262.2, found 262.4.

[0093] Intermediate PH2: 1-(2-azidopropyl)-4-(2-methoxyphenyl)piperazine

[0094] Synthesis of intermediate P7 Using intermediate 10b (906mg, 3...

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Abstract

The invention relates to environment-sensitive alpha1-adrenergic receptor near infrared fluorescence ligands and an application thereof. The ligands are represented by general formula (I); and in the formula (I), R1 is a pharmacophore quinazoline or phenylpiperazine, R2 is a different substituent, X is a linker (carbon chain or triazole ring) of different types, n1 represents the carbon number and is 1-6, and X2 is an iodide or bromide ion. The molecules of the fluorescence ligands have high affinity to an alpha1-adrenergic receptor, and the fluorescence does not substantially enhance with the polarity decrease or viscosity increase of surrounding environment. When the ligand molecules are combined with the alpha1-adrenergic receptor, the molecules enter hydrophobic environment and release a strong fluorescence signal, so visualization is easily realized, and the signal to noise ratio is good. The fluorescence ligands can be used in researches of the pharmacologic and physiological characteristics of the alpha1-adrenergic receptor as a tool drug. A preparation method of like compounds has the advantages of maturation, mild reaction conditions, cheap and easily available raw materials, and convenient operation and post-treatment.

Description

technical field [0001] The invention belongs to the technical field of medicines, in particular to a class of environment-sensitive alpha 1 - Adrenergic receptor near-infrared fluorescent probe and its 1 Applications in pharmacology and physiology studies such as adrenergic receptor cell imaging, subcellular localization and expression level detection. Background technique [0002] G-protein-coupled receptors with seven transmembrane structures are the largest family of cell surface receptors, and their coding genes account for about 4% of the human protein-coding genome [Zhang, R.; Xie, X. Tools for GPCR drug discovery. ActaPharmacol. Sin. 2012, 33, 372-84.]. As multifunctional molecular machines, G-protein-coupled receptors regulate most physiological responses mediated by hormones and neurotransmitters and are the target of nearly 26% of marketed prescription drugs. Although gratifying progress has been made in the chemical and structural biology of G-protein coupled r...

Claims

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Application Information

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IPC IPC(8): C09K11/06C07D403/14G01N21/64G01N15/10A61K49/00
Inventor 李敏勇杜吕佩马朝
Owner SHANDONG UNIV
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