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Alkaloid compound with 1,2,3-triazole structure segment and application of compound

A technology of structural fragments and compounds, applied in the field of alkaloid compounds, can solve the problems of poor cell penetration ability and unsatisfactory cell level activity of peptide compounds

Inactive Publication Date: 2016-07-13
UNIV OF JINAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Based on this structural basis, two research groups, Well and Hu, designed a series of peptides. However, the poor cell penetration of peptide compounds leads to unsatisfactory cell-level activity (Org. Biomol. Chem., 2013, 11, 3553; Bioorg .Med.Chem.Lett.2013,23,3029)

Method used

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  • Alkaloid compound with 1,2,3-triazole structure segment and application of compound
  • Alkaloid compound with 1,2,3-triazole structure segment and application of compound
  • Alkaloid compound with 1,2,3-triazole structure segment and application of compound

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] The preparation of formula 2-1 compound

[0024]

[0025] 5.0g formula 1-1 compound and 2.57g trimethylsilyl acetylene are dissolved in 25mLN, in the mixed solution of N-dimethylformamide and 5mL triethylamine, nitrogen protection, add 1.53g tetrakis (triphenylphosphine subsequently) ) palladium and 0.4g cuprous iodide, heated to 50 o C and stirred at this temperature for 6 hours. Afterwards, the reaction solution was concentrated, and the organic phase was extracted with ethyl acetate / water. The organic phase was washed successively with water and saturated brine, and concentrated. The residue was purified by column chromatography to obtain 3.90 g of compound Formula 2-1 as a colorless oil, with a yield of 73%. 1 HNMR (400MHz, CDCl 3 )δ7.84(1H,d,J=9Hz),7.34(1H,s),7.31(1H,d,J=9Hz),3.88(3H,s),2.56(3H,s),0.25,(9H ,s). 13 CNMR (100MHz, CDCl 3 )δ167.4, 140.2, 135.0, 130.5, 129.2, 129.0, 126.7, 104.1, 96.9, 51.9, 21.5, 0.2.

Embodiment 2

[0027] The preparation of formula 3 compound

[0028]

[0029]Dissolve 3.90g of the compound of formula 2-1 in 50mL of methanol, ice bath to 0 o C, add 2.48g potassium hydroxide. After the reaction was carried out for 2 hours, it was heated to reflux for 4 hours. After the reaction solution was concentrated under reduced pressure, 50 mL of water was added, and the aqueous phase was extracted three times with ethyl acetate. Afterwards, the aqueous phase was acidified to pH~3 with 10% hydrochloric acid solution, and extracted three times with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate, saturated brine, and water successively, and dried over anhydrous magnesium sulfate. Finally, after filtration and concentration of the organic phase, 2.5 g of light yellow solid compound Formula 3 was obtained, with a yield of 98%. It can be directly used in the next reaction. 1 HNMR (400MHz, CDCl 3 )δ8.03(1H,d,J=8Hz),7.41(1H,s),7.39(1H,d,J=8Hz),3.22(1H,...

Embodiment 3

[0031] The preparation of formula 4 compound

[0032]

[0033] Dissolve 2.50g of the compound of formula 3 in 30mL of dichloromethane, ice bath to 0 o C, followed by the addition of 2.33 g HOBT, 4.1 mL N,N-diisopropylethylamine (DIEPA) and 3.28 g EDCI. After the reaction was carried out for 0.5 hour, 4.06 g and 2-morphine ethylamine were added. The reaction was stirred overnight, and the organic phase was washed successively with saturated brine and water, and dried over anhydrous magnesium sulfate. Filter and concentrate to obtain a residue. The residue was purified by column chromatography to obtain 3.60 g of white solid compound Formula 4 with a yield of 85%. 1 HNMR (400MHz, CDCl 3 )δ7.32(2H,d,J=12Hz),7.31(1H,s),6.41(1H,s),3.68(4H,dd,J=4,4Hz),3.51(2H,m),3.11( 1H,s),2.36(2H,t,J=4Hz),2.47(4H,m),2.41(3H,s). 13 CNMR (100MHz, CDCl 3 )δ169.2, 136.7, 136.1, 134.5, 129.4, 126.9, 123.6, 82.8, 78.3, 66.8, 56.9, 53.3, 35.9, 19.6. ESI-MS: 273.0 [M+H + ]

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Abstract

The invention discloses an alkaloid compound with a 1,2,3-triazole structure segment and application of the compound.The compound has the general structural formula as shown in the description.The alkaloid compound with the 1,2,3-triazole structure segment is novel in structure, synthetic route operation is easy and convenient, the yield is high, and the safety is good.It is proved through experiments that the compound has certain inhibitory activity on Keap1-Nrf2 protein and protein interaction, and it is promoted through research results that the compound has potential application in the drug research field of tumor resistance, inflammation resistance, Parkinson's disease resistance and Alzheimer's disease resistance.

Description

technical field [0001] The invention relates to an alkaloid compound having a 1,2,3 triazole structural fragment and its use in the preparation of drugs for preventing and / or treating tumors, inflammation, anti-Parkinson's disease and anti-senile dementia. Background technique [0002] Oxidative stress directly or indirectly damages the physiological functions of intracellular proteins, lipids, nucleic acids and other macromolecules, and is considered to be related to the occurrence of more than 200 diseases, such as tumors, inflammation, Parkinson's disease and Alzheimer's disease Wait. The body has formed a complex oxidative stress response system. When exposed to electrophilic reagents or active oxygen stimulation, a series of protective proteins can be induced to alleviate the damage of cells. Nrf2 (nuclear factor E2-related factor 2) is a key factor in cellular oxidative stress response and is regulated by Keap1 (Keleh-like epichlorohydrin-related protein-1) protein (F...

Claims

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Application Information

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IPC IPC(8): C07D249/06A61K31/5377A61P35/00A61P25/16A61P25/28A61P29/00
CPCC07D249/06
Inventor 江成世张华张娟刘娜李家诚
Owner UNIV OF JINAN
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