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Photo-induced multifunctional cross-linking agent, preparation method and application thereof

A compound and selected technology, applied in the field of protein cross-linking and protein analysis research, can solve the problems of mass spectrometry analysis and protein interaction confirmation, difficulty in synthesis of structural specificity, complex structure of cross-linked peptides, etc. Reaction efficiency, good ability to capture interacting proteins, effect of good reactivity

Pending Publication Date: 2021-03-30
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Therefore, these photocross-linking agents are not selective, and the cross-linked peptides produced by the corresponding protein cross-linking technology have complex structures, difficult to analyze mass spectrometry data, and high false positives, which bring problems to subsequent mass spectrometry analysis and confirmation of protein interactions very difficult
At the same time, the above-mentioned four types of photoactive functional groups are difficult to synthesize due to their special structure.

Method used

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  • Photo-induced multifunctional cross-linking agent, preparation method and application thereof
  • Photo-induced multifunctional cross-linking agent, preparation method and application thereof
  • Photo-induced multifunctional cross-linking agent, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 6

[0155] Example 6: N-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexyl)-4-(hydroxymethyl)-3-nitrobenzyl Amide

[0156]

[0157] Step 1-1: Dissolve 4-bromomethyl-3-nitrobenzoic acid (5.0 g, 19.31 mmol, 1.0 eq) in 60 mL of acetone, add 60 mL of water, and stir well. Anhydrous sodium carbonate (7.16 g, 67.58 mmol, 3.5 eq) was then added. The resulting mixture was reacted at 70°C for 2 hours. The reaction was monitored by LC-MS. After the reaction was completed, the pH was adjusted to 3-4 with 2N hydrochloric acid, extracted with ethyl acetate, dried, and the solvent was spun off to obtain 4.02 g of compound 1D as a yellow solid, which was directly injected into the next step without further purification. 1 H NMR (400MHz, CDCl 3 )δ8.79(d, J=1.6Hz, 1H), 8.36(dd, J=8.1, 1.7Hz, 1H), 7.96(d, J=8.2Hz, 1H), 5.11(s, 2H).

[0158] Step 1-2: Compound 1A (54 mg, 0.275 mmol) was added to 2:1 CH 2 Cl 2 and trifluoroacetic acid (1.5 mL), stirred at room temperature for 1 h and the solven...

Embodiment 223

[0160] Example 223: N-(6-(2-Bromoacetamido)hexyl)-4-(hydroxymethyl)-3-nitrobenzamide

[0161]

[0162] Step 2-1: Dissolve 2-bromoacetic acid (2.00g, 14.39mmol) in anhydrous 1,4-dioxane (15mL), add NHS (1.66g, 14.39mmol), dropwise at 0°C A solution of DCC (3.27 g, 15.83 mmol) in anhydrous 1,4-dioxane (5 mL), the reaction mixture was stirred at room temperature for 2 h and filtered, the filtrate was concentrated in vacuo to give compound 2A as a yellow oil (2.43 g, 77% ). 1 H NMR (400MHz, DMSO) δ4.64(s, 2H), 2.83(s, 4H).

[0163]Step 2-2: Compound 1D (400 mg, 2.03 mmol), HATU (849 mg, 2.23 mmol) and tert-butyl(6-aminohexyl) carbamate (483 mg, 2.23 mmol) were added in dry DMF (10 mL) DIPEA (1 mL, 6.09 mmol) was added dropwise at 0°C, and the mixture was stirred at room temperature overnight. Add H to the mixture 2 O, and extracted 3 times with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated in vacuo. The residue w...

Embodiment 229

[0165] Example 229: 4-(2-(4-(Hydroxymethyl)-3-nitrobenzamido)ethyl)phenylfluorothioate

[0166]

[0167] Step 3-1: Compound 1D (1.00 g, 5.07 mmol) and NHS (702 mg, 6.08 mmol) were dissolved in DMF (15 mL), EDCI·HCl (1.16 g, 6.08 mmol) was added, and the reaction mixture was stirred at room temperature for 2 h. Add H to the mixture 2 O, and extracted 3 times with ethyl acetate. Organic layer with 2.8% KHSO 4 , washed with brine, washed with anhydrous Na 2 SO 4 Dry and concentrate in vacuo. The residue was purified by silica chromatography to give the product Compound 3A (710 mg, 48%) as a yellow oil.

[0168] Step 3-2: Fill chamber A of a dry two-chamber reaction flask with 1,1'-sulfonimidoimidazole (SDI, 1.487g, 7.5mmol) and potassium fluoride (KF, 1.162g, 20.0mmol) . Next, compound 3B (1.18 g, 5.0 mmol), triethylamine (1.53 mL, 11.0 mmol) and dichloromethane (DCM, 4 mL) were added in chamber B. Finally, 15 mL of a trifluoroacetic acid (TFA) / water mixture was inject...

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Abstract

The invention relates to a photo-induced multifunctional cross-linking agent as shown in a general formula (I), wherein the photo-induced multifunctional cross-linking agent is mainly applied to biomacromolecule interaction, such as protein-protein interaction and protein-nucleic acid interaction. According to the invention, the cross-linking agent can be used in biological samples or cells of cell lysis solutions to capture protein-protein interaction or protein-nucleic acid interaction, and can be applied to subsequent protein enrichment and protein cross-linking mass spectrometry; and the photo-induced multifunctional cross-linking agent has important application potential and practical value in interaction research of biomacromolecules.

Description

technical field [0001] The invention belongs to the technical field of protein crosslinking and protein analysis research, and mainly relates to the preparation of a light-induced multifunctional crosslinking agent and its application in protein interaction and protein mass spectrometry analysis. Background technique [0002] Protein is the executor of cell activity and function, and the function of protein depends on the interaction between protein and protein. Protein interaction plays an important role in the processes of apoptosis and necrosis, metabolism, growth and reproduction, etc. At the same time, abnormal protein interaction will also affect the activity and function of cells, which will lead to many diseases, such as neurodegenerative diseases and cancer. Wait. Therefore, finding and discovering new protein functions and new protein-protein interaction networks is a basic research issue that has been concerned in the field of life sciences, and it is also a basi...

Claims

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Application Information

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IPC IPC(8): C07D207/452C07D207/448C07D311/18C07D207/46C07C247/12C07C247/04C07C247/16C07C247/18C07C319/20C07C319/22C07C323/52C07C323/25C07C265/12C07C231/12C07C237/04C07C221/00C07C225/06C07C237/32C07C273/18C07C275/24C07C269/06C07C271/16C07C201/12C07C205/34C07D213/71C07C235/78C07C327/22C07C205/43C07C243/28C07C323/60C07D203/04C07D339/04C07C257/06C07D213/82C07D495/04C07K1/14G01N33/68
CPCC07D207/452C07D207/448C07D311/18C07D207/46C07C247/12C07C247/04C07C247/16C07C247/18C07C323/52C07C323/25C07C265/12C07C237/04C07C225/06C07C237/32C07C275/24C07C271/16C07C205/34C07D213/71C07C235/78C07C327/22C07C205/43C07C243/28C07C323/60C07D203/04C07D339/04C07C257/06C07D213/82C07D495/04C07K1/14G01N33/6848
Inventor 陈小华聂辉军闫克念周宾山冯磊
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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