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Preparation and medical application of binary structure sinomenine derivatives

A dual structure, sinomenine technology, applied in the field of medicine, to achieve the effect of novel structure

Inactive Publication Date: 2017-08-04
JIANGSU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But so far there is no report on the preparation method of sinomenine derivatives with dual structural characteristics of morphinane alkaloids and phenylpropanoids and the prevention and treatment of neurodegenerative diseases

Method used

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  • Preparation and medical application of binary structure sinomenine derivatives
  • Preparation and medical application of binary structure sinomenine derivatives
  • Preparation and medical application of binary structure sinomenine derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Embodiment 1: the preparation of 1-iodosinomenine

[0031]

[0032] Dissolve 990 mg (3 mmoL) of sinomenine in 20 mL of dichloromethane (DCM), add 739.5 mg (3.3 mmoL) of NIS in two portions, stir at room temperature for 4 h, and detect by TLC until the reaction is almost complete. After most of the solvent was evaporated, 50 mL of ethyl acetate was added, and 2×20 mL of NH 4 Cl water was washed, and the organic layer was washed with 20 mL of saturated brine and washed with anhydrous Na 2 SO 4 After drying, the solvent was evaporated and purified by silica gel column (CHCl 3 :CH 3 OH=10:1), 835.0 mg of light yellow solid 1-iodosinomenine was obtained, the yield was 84.6%, ESI-MS: m / z 456.1 [M+H] + .

Embodiment 2

[0033] Example 2: Preparation of binary structure sinomenine derivatives

[0034]

[0035] 1.41 g (3.1 mmol) of 1-iodosinomenine, triphenylphosphine (PPh 3 ) 280 mg (0.31 mmol), palladium acetate (Pd(OAc) 2 ) 35 mg (0.16 mmol) was added to 35 mL DMF-triethylamine (DMF-Et 3 N) (3:1) in the mixture, add N after evacuating for 15 min 2 , then evacuate for 15 min, inject 1.8 mL (5 eq) of ethyl acrylate and add N 2 , reacted at 80°C for 3 h. After the reaction, add 80 mL of water, extract with 100 mL×3 ethyl acetate, combine the organic layers and wash with 50 mL×3 saturated brine, combine the aqueous layers for 3 times, extract with 50 mL ethyl acetate, and extract all the organic layers Combine and dry. Most of the solvent was evaporated to 10 mL, and it was left to stand in the refrigerator overnight, and 0.5 g of a light yellow solid was precipitated. After the mother liquor was evaporated to dryness, it was purified by a silica gel column to obtain 0.4 g of a solid, an...

Embodiment 3

[0051] Example 3: Inhibition of NF-κB Activity by Binary Sinomenine Derivatives

[0052] The 293 cells stably transfected with pNF-κB-luc (Shanghai Institute of Cell Biology, Chinese Academy of Sciences) were used at 1×10 5 The cells / well were inoculated into 96-well plates, and 12.5 and 50 μg / mL of drugs or DMSO were added, respectively. After adding the drugs for 15 minutes, 10 μg / mL of LPS was added to stimulate the cells for 6 hours. The luciferase activity was determined with a kit (Promega). The luminescence value was detected on the computer (Berthold Company, Sirius single-tube light detection system). Triptolide (LGT, China National Institute of Pharmaceutical and Biological Products, purity ≥ 99%) was used as a positive control. See Table 1 for specific data.

[0053] Table 1. Inhibitory effects of sinomenine and its derivatives on NF-κB signaling pathway

[0054]

[0055] ** p * p a) blank control, b) positive control

[0056] Some derivatives have si...

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Abstract

The invention relates to preparation and a medical purpose of a dual structure sinomenine derivative, in particular relates to synthesis of the dual structure sinomenine derivative and application of the dual structure sinomenine derivative in preparing anti-inflammatory and neurodegenerative disease resistant medicines and belongs to the technical field of medicines. The dual structure sinomenine derivative is prepared by the following steps: with sinomenine or a sinomenine structural analog as a raw material, carrying out reaction on the sinomenine or the sinomenine structural analog and N-iodosuccinimide (NIS) to prepare 1-iodo sinomenine or sinomenine structural analog; and further, by virtue of Heck reaction, carrying out coupling on the 1-iodo sinomenine or sinomenine structural analog and acrylate to obtain a 1-acrylate substituted dual sinomenine derivative. The dual structure sinomenine derivative is adopted to carry out enzyme, cell and mouse drug effect tests, and a result shows that the dual structure sinomenine derivative is capable of inhibiting NF-kappa B expression, resisting inflammation, protecting PC12 neurons, lowering the quantity of NO, released by microglia BV-2, and strengthening activities including telomerase and has good potential of resisting inflammation and neurodegenerative diseases and clinical application value.

Description

technical field [0001] The present invention relates to the preparation and medical use of binary structure sinomenine derivatives, in particular to the synthesis of binary structure sinomenine derivatives and their application in the preparation of anti-inflammatory and anti-neurodegenerative disease drugs, belonging to the field of medical technology . Background technique [0002] Sinomenine (sinomenine, abbr. sino, formula 1) is mainly used clinically to treat rheumatism, rheumatoid arthritis and ankylosing spondylitis and other difficult-to-cure inflammations. Three common botanicals for rheumatoid arthritis. Sinomenine exerts a significant anti-inflammatory immune effect by regulating the activity of immune cells, NF-κB signaling pathway and related inflammatory factors (Wang, Y, et al., J. Ethnopharm., 2005, 98(1-2): 37-43; Zhao, Y, et al., Int. Immunopharmacol., 2007, 7(5): 637-645), and also has biological activities such as anti-tumor, neuroprotection and detoxif...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D221/28A61K31/485A61P29/00A61P25/16A61P25/28
CPCC07D221/28
Inventor 汤建姜春保欧阳臻许化溪苏兆亮冯建科
Owner JIANGSU UNIV
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