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Friedelane type compound as well as preparation method and application thereof

The technology of a compound and a deuterated compound, which is applied in the field of suberane-type compounds and their preparation, can solve the problem that the inhibitory effect cannot meet the demand and the like, and achieves the effects of a green preparation method, improved effect, and strong inhibitory effect.

Active Publication Date: 2022-04-15
FUJIAN UNIV OF TRADITIONAL CHINESE MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, the inhibitory effect of Tripterygium wilfordii on STAT3 can not meet the demand, and a new compound with more excellent inhibitory effect on STAT3 has been developed to treat STAT3 Activity-related diseases are important

Method used

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  • Friedelane type compound as well as preparation method and application thereof
  • Friedelane type compound as well as preparation method and application thereof
  • Friedelane type compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Embodiment 1, preparation compound CEL-2

[0039]

[0040]Step 1: Take 400mg tripterine, dissolve it in 40ml absolute ethanol, and prepare a 10mg / ml substrate solution. The two-step culture method was used in soybean meal liquid medium (recipe: commercially available soybean meal 5g, glucose 20g, yeast extract 5g, NaCl 5g, K 2 HPO 4 5g, distilled water to 1L) to culture Streptomyces griseus to the logarithmic growth phase (cultivation conditions are 28 ℃, shaker speed 180rpm / min), then add the above substrate solution (control the final concentration of tripterine to 15mg / min). 250mL), continue to cultivate for 4 days and then finish the fermentation, take the fermentation supernatant and extract 3 times with an equal volume of ethyl acetate, recover the organic solvent under reduced pressure, and obtain the fermentation product containing compound CEL-2.

[0041] Step 2: The fermentation product obtained in Step 1 is separated and purified by silica gel column chr...

experiment example 1

[0044] Experimental example 1, the specific inhibitory effect of compound CEL-2 on STAT3

[0045] 1. Experimental method

[0046] In this experiment, Western blot was used to analyze the effect of CEL-2 on STAT3 phosphorylation and its downstream proteins (Survivin, MCL-1) and its upstream proteins (JAK-2, p-JAK-2) in HCT-116 cells function, the specific method is as follows:

[0047] IL-6 stimulation was used to induce inflammation in HCT-116 cells. HCT-116 cells were cultured in RPMI / 1640 medium containing 10% FBS. When the cells grew to the logarithmic growth phase, they were digested with 0.25% EDTA trypsin Cells were collected by centrifugation (1200rpm / min for 4min) and diluted 1:3 for passage.

[0048] (1) Detect the inhibitory effect of tripterine (CEL) and CEL-2 on HCT-116 cells by CCK-8 method, and calculate the IC of CEL and CEL-2 on HCT-116 cells 50 , after routine digestion and centrifugation of HCT-116 cells, adjust the concentration of the cell suspension to ...

experiment example 2

[0058] Experimental example 2, the binding dissociation constant of test compound CEL-2 and STAT3

[0059] 1. Experimental method

[0060] In this experiment example, the surface plasmon resonance technology is used to analyze the interaction mode between CEL-2 and STAT3. The specific method is as follows:

[0061] (1) According to the ligand pre-enrichment, select the best concentration of human STAT3 recombinant protein and the most suitable pH condition, dissolve the STAT3 protein in buffers with different pH, and when it flows through the surface of the chip, it can be electrostatically adsorbed. Bind to the carboxyl group on the surface of the CM5 chip, mix 500μg / mL STAT3 protein with different pH sodium acetate buffer (10mM, pH4.5, 5.0, 5.5) to make the final protein concentration 10μg / mL, if there are bubbles , can be removed by centrifugation. The protein solution prepared with different pH sodium acetate buffer was injected onto the CM5 sensor chip, and its binding ...

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Abstract

The invention discloses a frietane type compound as well as a preparation method and application thereof, and belongs to the technical field of medicines. The compound can significantly inhibit STAT3 phosphorylation of colon tumor cells and downstream proteins thereof, has good affinity with human-derived STAT3 recombinant proteins, can be used for preparing STAT3 small-molecule inhibitors, and can be used for preparing drugs for preventing and / or treating STAT3 activity-related diseases. Compared with tripterine, the compound disclosed by the invention has the advantages that the effect of inhibiting STAT3 protein phosphorylation is obviously improved, and the activity of inhibiting HCT-116 colorectal cancer cell proliferation is stronger. The compound provided by the invention can promote HCT-116 colorectal cancer cell apoptosis and retard the cell cycle, has a stronger inhibition effect on the activity of colorectal cancer organs than a positive drug oxaliplatin, is basically non-toxic to normal colorectal organs, and can be used for preparing drugs for treating colorectal cancer. The preparation method of the compound is green, environment-friendly, high in yield and suitable for expanded production.

Description

technical field [0001] The invention relates to a suberane-type compound, a preparation method and application thereof, and belongs to the technical field of medicine. Background technique [0002] STAT3 is a cytoplasmic transcription factor that regulates biological functions including cell proliferation, differentiation, survival, angiogenesis, and immune response by regulating the transcription of a variety of genes. STAT3 is an important member of transcriptional signal transducers and activators. Its continuous activation can upregulate cell cycle regulators and anti-apoptotic proteins in tumor cells, promote abnormal proliferation and malignant transformation of tumors, and play an important role in the occurrence and development of various cancers. had an important impact. Recent studies have shown that under normal physiological conditions, the activation of STAT3 protein is strictly controlled; while in a variety of tumors (such as breast cancer, ovarian cancer, sq...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J63/00A61K31/56A61P35/00C12P33/00C12P33/06C12R1/545
CPCC07J63/008C12P33/00C12P33/06A61K31/56A61P35/00Y02P60/87
Inventor 许少华徐伟范若兰
Owner FUJIAN UNIV OF TRADITIONAL CHINESE MEDICINE
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