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Evodiamine prodrug containing indolequinone unit, and preparation method and application thereof

A technology of evodiamine and hydroxyevodiamine, which can be used in organic chemistry, drug combination, antitumor drugs, etc., and can solve problems such as lack of specificity

Active Publication Date: 2021-10-29
SHAANXI UNIV OF CHINESE MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, it lacks specificity and is limited by undesirable toxicity and side effects

Method used

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  • Evodiamine prodrug containing indolequinone unit, and preparation method and application thereof
  • Evodiamine prodrug containing indolequinone unit, and preparation method and application thereof
  • Evodiamine prodrug containing indolequinone unit, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Synthetic example

[0034] 5-methoxy-2-methyl-1H-indole-3-aminomethyde (2). POCL will be used under stirring 3 (0.85 ml, 9.28 mmol) was added to DMF (N, N-dimethylformamide, 3.0 mL, 38.9 mmol) cooled to 0 ° C. After the addition, the Vilsmeier reagent was continued at 0 ° C for 15 minutes. 5-methoxy-2-methylindole (1.04 g, 6.45 mmol) was dissolved in 3 ml no water DMF, and cooled to 0 ° C, and previously prepared Vilsmeier reagents were added. After the addition was completed, the reaction was stirred at 0 ° C for 30 minutes, TLC point plate detection, after the reaction was completed, the reaction liquid was added to 2 m NaOH (50 mL) aqueous solution of 0 ° C, add DCM (dichloromethane, 100 mL) and Extraction separation. The aqueous layer was extracted again with DCM (50 mL). Combined with organic layers, washed with saturated brine, and use NA 2 SO 4 dry. The solvent was removed, and the residue was washed with a cooled EtOAc to give 1.05 g (86%) of Compound 2, which is a light brown solid. 1 H NMR ...

Embodiment 1

[0046] The synthesis of Compound 8a. Dikaric anhydride (51 mg, 0.51 mmol) was dissolved in DCM (2 mL), and DMAP (41.5 mg, 0.34 mmol) was added as a catalyst, and after stirring for 30 minutes, Compound 7 (40 mg, 0.17 mmol) was added, continued at room temperature. Stir 12 hours. Then washed with 10% by weight of hydrochloric acid (20 mL) and extracted with DCM (20 mL × 3). The combined organic layer was washed with saturated brine (20 mL) and used NA 2 SO 4 dry. After removing the solvent, the column chromatography was purified, eluted with EtOAc / petroleum ether (1: 1, RF = 0.21) to give a compound 8a (yield 73%) in the form of a red solid.

[0047] Synthesis of Compound 8b. Pentanic anhydride (58.2 mg, 0.51 mmol) was dissolved in DCM (2 mL), and DMAP (41.5 mg, 0.34 mmol) was added as a catalyst. After conventional stirring for 30 minutes, Compound 7 (40 mg, 0.17 mmol) was added, at room temperature. Stirring is stirred for 12 hours. Then washed with 10% by weight of hydrochlori...

Embodiment 2

[0056] The chemical structural formula of 10-OH-EVO is as follows:

[0057]

[0058] The synthesis of Compound 9a. 10-OH-EVO (15.95 mg, 0.05 mmol) was dissolved in DCM (2 mL), and DMAP (6.1 mg, 0.05 mmol) was added as a catalyst to the mixture. After completion, stirred at 0 ° C, adding compound 8a (12 mg, 0.05 mmol) and EDCI (0.25 mmol), and stirred at room temperature for 24 hours. The reaction mixture was then washed with 10% hydrochloric acid (20 mL) and extracted with DCM (20 mL × 3). The combined organic layers were washed with saturated sodium hydrogencarbonate (20 mL) and saturated brine (20 mL) and used NA 2 SO 4 dry. After removing the solvent, the residue was purified on silica gel, using DCM / CH 3 OH (4%, RF = 0.32) was eluted to afford the compound 9a (58% yield), which is a light red brown solid.

[0059]Synthesis of Compound 9b. 10-OH-EVO (15.95 mg, 0.05 mmol) was dissolved in DCM (2 mL), and DMAP (6.1 mg, 0.05 mmol) was added as a catalyst to the mixture. After ...

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Abstract

The invention relates to an evodiamine prodrug containing an indolequinone unit, and a preparation method and application thereof. According to the present invention, a series of the evodiamine derivatives having the strong activity and having the indolequinone unit are synthesized, and the evodiamine derivatives have the strong anti-proliferation activity on non-small cell lung cancer (NSCLC), and have the dose and time dependence; and in-vitro experiments evaluate the biological activity of the compounds, which shows that the synthesized compounds have strong inhibitory activity on lung cancer strains. Through molecular docking analysis, the binding affinity of the ligand and the active site of the target protein is predicted, and the interaction capacity with the protein is relatively strong.

Description

Technical field [0001] The invention belongs to the pharmaceutical technique, and more particularly to Wu Hao base prodrug containing hydrazine unit and its preparation method and application thereof. Background technique [0002] It is generally believed that Chinese medicine has the effect of gaining attenuation. At present, Chinese medicine is an important part of cancer comprehensive treatment, and it is an indispensable role in various stages of lung cancer treatment [QI, F., L. Zhao, A. Zhou, et al., The advantages of using Traditional Chinese Medicine As An AdjunctiveTherapy In The Whole Course of Cancer Treatment Instead of Only TerminalStage of Cancer. Biosci Trends, 2015.9 (1): p. 16-34]. Various Chinese herbal medicines include herbal compounds and their extracts have proven to play an important role in anti-cancer treatment in a variety of ways and targets [Li, ZY, WC Huang, RS TU, ET Al., Sophoraflavanone G INDUCES APOPTOSI Humanleukemia Cells and Blocks Mapk Activat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/14A61P35/00
CPCC07D471/14A61P35/00
Inventor 郭惠马晶晶王馨怡杨政
Owner SHAANXI UNIV OF CHINESE MEDICINE
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