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Sinomenine derivative as well as preparation method and application thereof

A technology of sinomenine and derivatives, applied in the field of sinomenine derivatives and their preparation, can solve the problems of limited anti-fibrosis effect of sinomenine, and achieve good anti-fibrosis effect, good safety, and anti-fibrosis Effect of effect improvement

Active Publication Date: 2022-04-29
广东克冠达医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The technical problem to be solved by the present invention is to overcome the defects and deficiencies of the limited anti-fibrosis effect of existing sinomenine, and provide a kind of sinomenine derivative

Method used

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  • Sinomenine derivative as well as preparation method and application thereof
  • Sinomenine derivative as well as preparation method and application thereof
  • Sinomenine derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] The preparation of embodiment 1 sinomenine derivatives

[0046]

[0047] The specific reaction steps for the preparation of the sinomenine derivatives are as follows:

[0048] S1. Compound (II) (20mmol, 1 equivalent) was dissolved in 160mL of dichloromethane, N-iodosuccinimide (21mmol, 1.05 equivalent) was added within 5 minutes, stirred at room temperature for 5 minutes, and 120mL Quenched with saturated sodium thiosulfate solution; extracted with dichloromethane, washed with brine, dried over magnesium sulfate, and evaporated under reduced pressure; the residue was purified by column chromatography to obtain compound (III) (yield: 86%);

[0049] S2, compound (III) (1mmol, 1 equivalent), 3-benzene-1-propyne (2mmol, 2 equivalents), ditriphenylphosphine palladium dichloride (0.05mmol, 0.05 equivalents), iodine Cuprous chloride (0.05mmol, 0.05eq), triethylamine (3mmol, 3eq) were dissolved in 10mL of anhydrous acetonitrile, stirred and reacted under argon protection fo...

experiment example 1

[0051] Experimental Example 1 Toxicity test (MTT method) of sinomenine derivatives to fibrotic cells

[0052] NIH / 3T3 cells (purchased from the Chinese Academy of Sciences) were placed in DMEM medium containing 10% fetal bovine serum at 37°C, 5% CO 2 cultured in a humidified incubator. Add 100 μL of NIH / 3T3 cells at a concentration of 7000 / well to each well of a 96-well culture plate, at 37°C, 5% CO 2 Cultivate for 24 hours; Add 100 μL / well of two-fold gradient dilution of the test drug to the drug experimental group, 6 replicate wells for each concentration, set up a cell blank control and positive drug control pirfenidone (Pirfenidone) at the same time, and continue to cultivate for 24 hours; After adding 10 μl of MTT and continuing to incubate for 4 h, the supernatant was discarded, 150 μl of DMSO was added, and the absorbance at 490 nm was detected with a full-wavelength multifunctional microplate reader. The toxic effect of compounds on fibrotic cells was determined.

...

experiment example 2

[0054] Experimental example 2 Inhibitory effect of sinomenine derivatives on TGF-β1-induced fibrosis target mRNA in NIH / 3T3 cells

[0055] NIH / 3T3 cells in the logarithmic growth phase (purchased from the Chinese Academy of Sciences) were selected to make a single cell suspension and seeded on a culture plate; the cells were stimulated with 5 ng / ml TGF-β1 for 24 hours to construct a fibrotic cell model. Divided into normal group, model group (TGF-β1 group), positive drug group (Pirfenidone group), sinomenine derivatives group (0.78, 1.56, 3.13, 6.25, 12.5μM), sinomenine group ( 0.78, 1.56, 3.13, 6.25, 12.5 μM).

[0056] Cells were collected, and total cellular RNA was extracted with an RNA extraction kit, reverse-transcribed into cDNA with an RNA reverse transcription kit, and PCR amplified using a SYBR Premix Ex TaqTM11 kit. The above experiments were performed in accordance with the instructions. The primers were synthesized by Sangon Biotechnology Co., Ltd., and the seque...

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Abstract

The invention belongs to the technical field of biological medicines, and particularly relates to a sinomenine derivative as well as a preparation method and application thereof. Experiments prove that the sinomenine derivative has no obvious toxic effect on cells and is relatively good in safety, and research finds that the sinomenine derivative achieves a remarkable anti-fibrosis effect by reducing the content of alpha-sma, cologen1 and fibronectin in vivo, and the anti-fibrosis effect is remarkably improved compared with sinomenine; even, the safety and the anti-fibrosis effect are better than those of a positive control drug, remarkable progress is achieved, and a brand-new anti-fibrosis drug is provided.

Description

technical field [0001] The invention belongs to the technical field of biomedicine. More specifically, it relates to a sinomenine derivative and its preparation method and application. Background technique [0002] Caulis Sinomenii (Caulis Sinomenii) is the dry vine of Sinomenium acutum (Thunb.) Rehd et Wils. and Sinamenium acutum (Thunb.) Rehd.et Wils.var.CinereumRehd.et Wils. stem. According to the 2015 edition of the Pharmacopoeia of the People's Republic of China, Qingfengteng tastes bitter and pungent, and is flat in nature. Mainly used for rheumatic arthralgia, joint swelling, numbness, itching. Because of its good therapeutic effect and less adverse reactions, it has been widely used in the treatment of rheumatoid arthritis and mesangial proliferative nephropathy. [0003] Sinomenine (SIN) is the main active ingredient in S. chinensis, which has analgesic, anti-inflammatory, immunosuppressive, anti-tumor effects, and is mainly used clinically for the treatment of ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D221/28A61P11/00A61P1/16A61P9/00A61P17/00A61P13/12A61K31/485
CPCC07D221/28A61P11/00A61P1/16A61P9/00A61P17/00A61P13/12
Inventor 刘洪恩
Owner 广东克冠达医药科技有限公司
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