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Hydrogen peroxide-responsive diazeniumdiolates and application thereof

A technology of azonium diols and salt compounds, applied in the field of medicinal chemistry, can solve the problems of lack of anti-tumor activity, lack of specificity, single structure, etc., and achieve rich species and potential biological value, strong universality, Responsive effect

Active Publication Date: 2019-12-17
JIANGNAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The currently reported H 2 o 2 Activated azonium dialkoxides are all based on H 2 o 2 The corresponding phenyl boronate structure has a single structure, poor stability, H 2 o 2 The problem of insufficient specificity, and the lack of detailed research on its anti-tumor activity

Method used

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  • Hydrogen peroxide-responsive diazeniumdiolates and application thereof
  • Hydrogen peroxide-responsive diazeniumdiolates and application thereof
  • Hydrogen peroxide-responsive diazeniumdiolates and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Embodiment 1: the synthesis of compound A

[0054] The first step: the synthesis of intermediate 1

[0055]

[0056] Specific operation: p-Nitroacetophenone (1g, 6.06mmol) was dissolved in pyridine (10mL), and SeO 2 (1g, 9.08mmol), where p-nitroacetophenone and SeO 2 The molar ratio is 1:1.5. Pass the mixture under nitrogen protection, stir at 90°C for 4 h, cool and filter after the reaction, wash the filter cake with ethyl acetate (EA) 3 times, collect the organic layer and wash it with 2M HCl, finally combine the organic layers, add anhydrous sulfuric acid After drying over sodium, the solvent was distilled off under reduced pressure and eluted by column chromatography (PE / EA v / v, 7:3) to obtain yellow intermediate 1.

[0057] The second step: the synthesis of intermediate 2

[0058]

[0059] Specific operation: Intermediate 1 (1g, 5.13mmol) was dissolved in tetrahydrofuran THF (10mL), and p-aminobenzyl alcohol (0.64g, 5.13mmol), EDCI (1.475g, 7.7mmol) and D...

Embodiment 2

[0075] Embodiment 2: the synthesis of compound B

[0076]

[0077] Azonium dialkoxide (71mg, 0.42mmol) and NaHCO 3 (23mg, 0.28mmol) was dissolved in anhydrous DMF (2mL), stirred at 0°C under nitrogen protection, then Intermediate 3 (100mg, 0.28mmol) was added, returned to room temperature and continued to stir for 1-2h. After the reaction, wash with water and saturated brine successively, combine the organic layers, add anhydrous sodium sulfate to dry, distill off the solvent under reduced pressure, column chromatography elution (PE / EA v / v, 6:4) to obtain the crude product, further pass DCM / EtOH recrystallization to obtain the target compound B (27%).

[0078] m.p.149–150°C.

[0079] 1 H NMR (400MHz, Chloroform-d) δ9.01(s,1H,NH),8.63–8.57(m,2H,ArH),8.38–8.33(m,2H,ArH),7.74–7.68(m,2H, ArH),7.48–7.42(m,2H,ArH),5.22(s,2H,ArCH 2 ),3.85–3.80(m,4H,OCH 2 ×2),3.43–3.37(m,4H,NCH 2 ×2).

[0080] 13 C NMR (100MHz, Chloroform-d) δ186.00, 157.91, 151.11, 137.68, 136.62, 133.08...

Embodiment 3

[0082] Embodiment 3: the synthesis of compound C

[0083]

[0084] Azonium dialkoxide (100mg, 0.42mmol) and NaHCO 3 (23mg, 0.28mmol) was dissolved in anhydrous DMF (2mL), stirred at 0°C under nitrogen protection, then Intermediate 3 (100mg, 0.28mmol) was added, returned to room temperature and continued to stir for 1-2h. After the reaction was completed, it was washed with water and saturated brine successively, the organic layers were combined, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the target compound C (47 %).

[0085] m.p.145–146°C.

[0086] 1 H NMR (400MHz, Chloroform-d) δ9.01(s,1H,NH),8.60–8.55(m,2H,ArH),8.36–8.30C(m,2H,ArH),7.72–7.67(m,2H ,ArH),7.44–7.38(m,2H,ArH),5.20(s,2H,ArCH 2 ), 4.13 (q, J=7.1Hz, 2H, OCH 2 ), 3.62 (dd, J=6.0, 4.4Hz, 4H, CONCH 2 ×2),3.41–3.28(m,4H,NCH 2 ×2), 1.25(t, J=7.1Hz, 3H, CH 3 ).

[0087] 13 C NMR (100MHz, Chloroform-d) δ185.95, 157.90, 155.18, 151.05, 137.63, 136.64, 132.9...

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Abstract

The invention discloses a hydrogen peroxide-responsive diazeniumdiolates and application thereof, belonging to the field of medicinal chemistry. The compound provided by the invention has high stability; the alpha-ketoamide structure of the compound can specifically respond to H2O2 to release NO; different structures can realize specific inhibition of different tumor cells; and the compound has low toxicity to normal cells, can be used as a novel NO donor type drug with high tumor cell selectivity and low toxic and side effects, and shows good market prospects.

Description

technical field [0001] The invention relates to a hydrogen peroxide-responsive azonium dialkoxide compound and application thereof, belonging to the field of medicinal chemistry. Background technique [0002] Nitric oxide (NO) has a wide range of physiological activities and also plays an important role in the field of anti-tumor. A large number of studies have shown that NO has dual effects on tumor cells: low concentration of NO can induce the mutation of apoptosis-related genes (such as p53), increase tumor cell drug resistance, promote tumor angiogenesis and metastasis, and promote tumor cell growth; high concentration NO can up-regulate the expression of tumor suppressor gene p53, promote the degradation of anti-apoptotic proteasome, increase the permeability of mitochondrial membrane, release cytochrome c (Cyt-c), induce apoptosis and cell cycle arrest, and exert anti-tumor activity . [0003] NO donor refers to a compound that can release NO through enzymatic or non...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/30C07D211/98A61P35/00A61K31/655
CPCA61P35/00C07D211/98C07D295/30
Inventor 傅俊杰尹健孟婷婷胡静
Owner JIANGNAN UNIV
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