Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Preparation method of K252c derivative and application of K252c derivative in preparation of anti-tumor metastasis medicine

A technology of derivatives and drugs, applied in the field of medicine, can solve the problems of not finding the relationship between ROCK2 inhibitors and anti-tumor metastasis, and the anti-tumor metastasis effect is not ideal, achieving significant anti-tumor metastasis effect, easy operation and implementation, synthesis Simple route effect

Pending Publication Date: 2021-12-10
ZHEJIANG UNIV
View PDF1 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, it has not been found whether there is an inevitable correlation between ROCK2 inhibitors and anti-tumor metastasis.
For example, there are currently only four approved ROCK inhibitor drugs, among which Fasudil, Ripasudil and Netarsudil are mainly used to treat glaucoma, ocular hypertension, etc., and Belumosudil is used to treat patients with chronic graft-versus-host disease over 12 years old , these marketed drugs are not effective in anti-tumor metastasis

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Preparation method of K252c derivative and application of K252c derivative in preparation of anti-tumor metastasis medicine
  • Preparation method of K252c derivative and application of K252c derivative in preparation of anti-tumor metastasis medicine
  • Preparation method of K252c derivative and application of K252c derivative in preparation of anti-tumor metastasis medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] The total synthesis of embodiment 1.THK01

[0053]

[0054]Weigh 10g (66mmol) of o-nitrobenzaldehyde (a, 2-nitro-benzaldehyde) and 21g (66mmol) of Phosphorus ylides into a 250mL reaction flask, add 50mL of anhydrous acetonitrile, and stir at reflux for 12h at 60°C . The progress of the reaction was detected by TLC until the disappearance of the raw materials, and the reaction product was concentrated under reduced pressure and separated by silica gel column chromatography (mobile phase was dichloromethane) to obtain light yellow solid b (12.6 g, 100%).

[0055]

[0056] Weigh 12.6g (66mmol) of product b into a three-necked reaction flask, and add 40mL of anhydrous dichloromethane to dissolve it. Connect the device so that the reaction system is filled with N 2 , add 26.7g (264mmol) triethylamine and 34.9g (132mmol) tert-butyldimethylsilyl trifluoromethanesulfonate (TBDMSOTf) dropwise successively, stir and reflux at 50°C for 4h, add triethylamine (6.7 g, 66mmol...

Embodiment 2

[0067] Example 2. Synthesis of Derivatives

[0068] According to the above synthetic route, the derivatives of THK01 are obtained by replacing the reaction substrate of Step1 or Step5, and the reaction conditions and purification methods are the same. The specific route can refer to the synthetic route.

[0069] THK04, THK05: THK04 and THK05 were obtained by reduction reaction of THK02, and the reduction products were prepared by HPLC high-pressure liquid phase (35% acetonitrile water, Agilent Pursuit C18 column, 10 μm, 21.2×250mm, which were used in the following unless otherwise specified) preparative column) to obtain white solid THK04 (t R =54min, productive rate 45%) and THK05 (t R =70 min, yield 44%).

[0070] THK06, THK07, THK08: Replace the substrate in the first step with o-nitro-m-methoxybenzaldehyde, and the rest of the operations are the same as for the synthesis of THK01. Separate through silica gel column chromatography to obtain THK06 (the 5th step reaction,...

Embodiment 3

[0079] Example 3. Identification of Compounds

[0080] THK01: white solid. HRESIMS gives the quasi-molecular ion peak as [M+H] + m / z328.1080 (calculated value is 328.1086), molecular formula is C 20 h 14 N 3 o 2 . 1 H NMR (600MHz, DMSO-d 6):δ11.78(1H,s),11.29(1H,s),8.96(1H,s),8.62(1H,d,J=2.5Hz),8.44(1H,s),8.01(1H,d, J=7.7Hz),7.74(1H,d,J=8.1Hz),7.49(1H,d,J=8.6Hz),7.45(1H,t,J=8.1Hz),7.28(1H,t,J=8.1Hz) 7.7Hz), 6.91(1H, dd, J=2.6, 8.6Hz), 4.93(2H, s). The spectrum data of the synthesized compound THK01 is consistent with the natural product obtained from the previous separation and extraction (Bioactive indolocarbazoles from the marine-derived Streptomycessp .DT-A61[J].J.Nat.Prod.2018,81,949-956.).

[0081] THK02: yellow solid. HRESIMS gives the quasi-molecular ion peak as [M+Na] + m / z 378.0848 (calculated value is 378.0855), molecular formula is C 21 h 13 N 3 o 3 . 1 H NMR (600MHz, DMSO-d 6 ): δ11.80(1H,s),11.63(1H,s),10.97(1H,s),8.99(1H,d,J=7.9Hz),8.58(1H,d,J=2....

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

PropertyMeasurementUnit
Cell concentrationaaaaaaaaaa
Login to View More

Abstract

The invention discloses application of a K252c derivative in preparation of a medicine for resisting breast cancer cell metastasis, and the structural formula of the K252c derivative is shown in the specification. The invention further discloses a preparation method of the K252c derivative, and the K252c derivative can be obtained by performing a Wittig reaction, a Diels-Alder reaction, a Cadolan reaction, a Fischer indole synthesis reaction, a demethylation reaction, a reduction reaction, a methylation reaction and the like on an initial substrate. The compound disclosed by the invention is simple in synthetic route, high in reaction yield and easy to operate and implement; and cell and animal level experiments show that THK01 has low toxicity to cells and can show a remarkable anti-tumor metastasis effect under a small dosage, and the effect of the THK01 is superior to that of an existing positive drug Y27632 in a clinical research and development stage.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a preparation method of a K252c derivative and an application in the preparation of an anti-tumor metastasis drug. Background technique [0002] Tumor metastasis is a complex and continuous biological process, including cells shed from the primary tumor lesion into the lymphatic and blood circulation, cells survive in the circulation, captured by new organs, penetrate into surrounding tissues, colonize new tissues and grow and proliferate . [0003] More than 90% of cancer deaths are related to tumor metastasis. However, due to insufficient understanding of the mechanism of tumor metastasis, breakthroughs in inhibiting tumor metastasis are very limited, and no successful drugs have been marketed yet. [0004] The inventor discovered a series of indolecarbazole natural products from the marine Streptomyces secondary metabolites in the early stage (refer to the patent specificati...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
IPC IPC(8): A61K31/407A61P15/14A61P35/04C07D487/14
CPCA61K31/407A61P15/14A61P35/04C07D487/14
Inventor 马忠俊王金慧丁婉婧章莹高婷婷
Owner ZHEJIANG UNIV
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com