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First glass photoaffinity labeling difunctional probe molecule and preparation method and application thereof

A probe molecule, labeled double technology, applied in live or field

Inactive Publication Date: 2012-07-04
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The complexity of this system may be limiting the widespread use of ABPP for GABA B Main Reasons for Receptor Research

Method used

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  • First glass photoaffinity labeling difunctional probe molecule and preparation method and application thereof
  • First glass photoaffinity labeling difunctional probe molecule and preparation method and application thereof
  • First glass photoaffinity labeling difunctional probe molecule and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation Embodiment 1

[0069] Preparation Example 1——Preparation of Compound 5

[0070] Preparation of compound 3

[0071]

[0072] Compound 1 (53mg, 0.12mmol, preparation reference Bioorg.Med.Chem., 1999, 7:2697-2704) was dissolved in 3mL of methanol, compound 2 (71mg, 0.13mmol, preparation reference J.Med.Chem., 2008 , 11:3057-3060) and i-Pr 2 NEt (92μl, 0.52mmol), the system was stirred overnight at room temperature in the dark, the solvent was spin-dried under reduced pressure and then purified by silica gel column chromatography, CHCl 3 :MeOH:H 2 Gradient elution of O=2:1:0-2:1:0.2 gave 68 mg of a colorless oily substance with a yield of 71.3%.

[0073] 1 HNMR (δ, ppm, CD 3 OD+CDCl 3 ): 1.42-1.90 (10H, m), 1.72 (3H, d, J=6.3Hz), 2.89-3.01 (2H, m), 3.35-3.38 (4H, m), 3.53 (2H, m), 3.63 ( 2H, m), 3.69(2H, m), 3.85(2H, s), 3.89(2H, m), 4.24(1H, m), 4.35(2H, m), 4.37(1H, q, J=6.9Hz ), 6.80(1H, s), 6.98(1H, d, J=8.4Hz), 7.47(1H, t, J=7.5Hz), 7.57(1H, d, J=7.2Hz), 7.99-8.08(3H , m).HR-ESI...

preparation Embodiment 2

[0078] Preparation Example 2——Preparation of Compound 7

[0079] Preparation of compound 6

[0080]

[0081] Rodamine B (500mg, 1.04mmol) was dissolved in dry DCM (25mL), DCC (430mg, 2.08mmol), HOBt (282mg, 2.08mmol) and propargylamine (100μL, 1.57mmol) were added sequentially under stirring. The reaction solution was stirred at room temperature for 18 h, and the solvent was spin-dried under reduced pressure, and purified by silica gel column chromatography, eluted with PE:EA=4:1 to obtain 311 mg of a white solid with a yield of 61.8%.

[0082] 1 HNMR (δ, ppm, CDCl 3 ): 1.15 (12H, t, J = 6.9Hz), 1.77 (1H, t, J = 2.4Hz), 3.34 (8H, q, J = 6.9Hz), 3.95 (2H, d, J = 2.4Hz), 6.28(2H, d, J=9.0Hz), 6.40(2H, s), 6.48(2H, d, J=9.0Hz), 7.10(1H, m), 7.43(2H, m), 7.93(1H, m ). 13 CNMR (δ, ppm, CDCl 3 )12.72, 28.62, 44.54, 64.90, 70.15, 78.40, 97.91, 105.20, 108.11, 123.10, 123.90, 128.11, 129.21, 130.54, 132.75, 148.97, 153.60, 153.88, 167.48

[0083] Preparation of compound 7

...

preparation Embodiment 3

[0087] Preparation Example 3——Preparation of Compound 9

[0088] Preparation of compound 8

[0089]

[0090] Protected HA (200 mg, 0.062 mmol) was dissolved in dry DCM (3 mL), EDC (23.8 mg, 0.125 mmol), Et 3 N (13 mg, 0.138 mmol), DMAP (1.5 mg, 0.0125 mmol) and propargylamine (17.2 mg, 0.312 mmol). The reaction solution was stirred at room temperature for 18 h, and the solvent was spin-dried under reduced pressure, and purified by silica gel column chromatography, CHCl 3 :MeOH=25:1, 78 mg of light yellow solid was eluted, and the yield was 76.2%.

[0091] 1 HNMR (δ, ppm, CDCl 3 ): 0.94 (3H, d, J=6.6Hz), 0.98-1.06 (6H, m), 1.15-1.30 (27H, m), 1.33-1.48 (18H, m), 1.70-2.30 (9H, m), 2.52-3.33(11H, m), 3.45-3.80(5H, m), 3.85-4.70(12H, m), 4.75-4.85(1H, m), 5.69(1H, t, J=6.3Hz), 5.78( 1H, t, J=7.2Hz), 6.76-7.00 (5H, m), 7.00-7.12 (3H, m), 7.12-7.22 (2H, m), 7.22-7.45 (5H, m), 7.45-7.67 ( 3H, m), 7.75 (2H, dd, J=10.8, 8.1Hz), 7.90 (1H, dd, J=15.6, 8.1Hz).ESIMS: m / z=843.6(M...

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Abstract

The invention relates to a first glass photoaffinity labeling difunctional probe molecule, which has combining ability of strong metabotropic (GABAB) receptor appetency and high selectivity, simultaneously can be used for remarking, tracking and analyzing dynamic change procedures of relevant signal albumen caused by activating or antagonism of the GABAB receptor on a living cell level pair film. The first glass photoaffinity labeling difunctional probe molecule is used for recovering novel target spots and studying protein spectrum, and provides direct, accurate and important information for diagnosis of diseases relevant to the GABAB receptor and development of corresponding psychotherapeutic drugs.

Description

technical field [0001] The invention relates to a class of photoaffinity labeled bifunctional probe molecules. The probe molecules involved in the present invention have γ-aminobutyric acid B-type receptors (Gamma Aminobutyric Acid B Receptor, referred to as GABA B R or GABA B receptor) strong affinity, highly selective binding ability, and can be used to bind GABA on the membrane at the level of living cells B Receptor labeling, tracing, and analysis of the dynamic change process of intracellular signaling proteins caused by activation or antagonism, as well as for the discovery of new targets and the study of protein profiles, for GABA B The diagnosis of receptor-related diseases and the development of corresponding therapeutic drugs provide more direct and accurate important information. The invention also relates to the structural design and preparation method of the probe molecules. Background technique [0002] The drug discovery process includes many stages, such ...

Claims

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Application Information

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IPC IPC(8): C07F9/6561C07F9/6558C07K7/06G01N33/68
CPCC07F9/65586C07F9/6561G01N2500/00G01N2333/70571C07F9/65583G01N33/9426
Inventor 南发俊刘剑峰陈林海林欣李新蒋明
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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