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Natural and synthetic isothiocyanate kind compound and its application in treating and preventing cancer

A technology of ester compound and isothiocyanate, applied in the preparation of natural and synthetic isothiocyanate compound JC-5411 in the prevention and treatment of prostate cancer, liver cancer, gastric cancer, lung cancer, breast cancer, cervical cancer, The application fields of drugs for melanoma and neuroblastoma can solve the problems of unstable chemical and drug metabolism properties, limiting the clinical use of malignant tumors, and toxic and side effects

Active Publication Date: 2009-01-07
JC (WUXI) CO INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] 3. The chemical and pharmacokinetic properties of HADC inhibitors currently in clinical trials are unstable
[0018] 6. Both the traditional nucleoside DNA methylation inhibitors and the newly discovered lidocaine, procaine and other clinically used antiarrhythmic or local anesthetics have serious toxic and side effects, which limits their treatment Clinical use in malignant tumors

Method used

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  • Natural and synthetic isothiocyanate kind compound and its application in treating and preventing cancer
  • Natural and synthetic isothiocyanate kind compound and its application in treating and preventing cancer
  • Natural and synthetic isothiocyanate kind compound and its application in treating and preventing cancer

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0061] Example 1, the synthesis of JC-5411

[0062]

[0063] 1 The H-NMR spectrum was measured with a Brucker AV-300 nuclear magnetic resonance instrument, the internal standard TMS, and the solvent was CDCl 3 ; MS was determined with a Nicolet FTMS-2000 mass spectrometer; elemental analysis was determined with an Elementar Vario EL III instrument.

[0064] Thin-plate chromatography (TLC) was self-made with silica gel GF254 (produced by Qingdao Ocean Chemical Factory); all reagents were commercially available chemically pure or analytically pure products, and were used directly without treatment.

[0065] Preparation of JC-5411 (Phenethyl Isothiocyanate, Phenethyl Isothiocyanate)

[0066] Into a 50 mL round bottom flask was added 15 mL of CH 2 Cl 2 and 3 mL (40 mmol) of thiophosgene, stirred, cooled to 0 ° C, and slowly added dropwise an equivalent amount of triethylamine (4.04 g, 40 mmol) and phenethylamine (4.85 g, 40 mmol) with a constant pressure dropping funnel. M...

example 2

[0068] Example 2, JC-5411 inhibits GSTP1 gene promoter DNA methylation:

[0069] Materials and methods:

[0070] Reagent: JC-5411 Phenethyl Isothiocyanate, synthesized by Wuxi Jesse Pharmaceutical Technology Co., Ltd. (see Example 1). During the experiment, the solution was prepared in DMSO. DNA polymerase chain reaction (PCR) reagents were purchased from Invitrogen Biotechnology Company, USA. PCR primers were purchased from Operon Biotechnology Company in the United States. Other chemical reagents used in the experiment were purchased from Sigma Chemical Reagent Company in the United States unless otherwise specified. Polyacrylamide gel reagents for protein electrophoresis, SDS, electrophoresis buffer, and protein electrotransfer buffer were purchased from Bio-Rad Life Sciences, USA.

[0071] Cell culture: Human prostate cancer cells LNCAP and PC-3 were purchased from American Type Culture Collection. Place cells at 37°C, 5% CO 2 In an incubator, culture in RPMI1640 medi...

example 3

[0079] Example 3, JC-5411 inhibits histone deacetylase:

[0080] Materials and methods:

[0081] Reagent: JC-5411, same as Example 2. Polyacrylamide gel reagents for protein electrophoresis, SDS, electrophoresis buffer, and protein electrotransfer buffer were purchased from Bio-Rad Life Sciences, USA. Site-specific acetylated and methylated histone H3 antibody was purchased from Upstate Biotechnology Company, USA. Unless otherwise specified, other chemical reagents used in the experiment were purchased from Sigma Chemical Reagent Company in the United States. Histone deacetylase (HDAC) activity assay kit was purchased from American Biomol Biochemical Technology Company.

[0082] Cell culture: with example 2.

[0083] Determination of histone acetylation and methylation: Human prostate cancer cells LNCAP in the logarithmic growth phase were treated with different concentrations of JC-5411 for 48 hours, and histones were separated by the method described by Yoshida et al. (...

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Abstract

The invention relates to naturally or artificially synthesized iso-thiocyanates i.e. JC-5411 compounds and their use in treating and preventing malignant tumor, wherein the compounds can directly suppress the methylation of the gene promoter / 5-UTR area CpG DNA, directly inhibit the reactivity of histone deacethylases (HADC), selectively promote histone acetylation and methylation, then further recover the expression of genes with important functions that are shut abnormally in cancer cells, thus control the malignant proliferation of cancer cells.

Description

technical field [0001] The invention belongs to the field of medical application (or chemical pharmacy), and relates to JC-5411 series compounds, which use isothiocyanate as the core structure, whether natural or synthetic, can directly inhibit abnormal DNA methylation in tumor cells The activity of histone deacetylase (histone deacetylase, HADC) selectively promotes histone acetylation and methylation, and then makes some genes with important functions that are abnormally closed in cancer cells, such as tumor suppressor genes , Regulating cell cycle, genes of apoptosis, genes of DNA damage and repair, genes that inhibit malignant invasion and metastasis of cancer cells, etc. restore expression and exert their normal functions, so that the malignant proliferation of cancer cells can be controlled, so that it can effectively It can effectively inhibit the growth of various human tumor cells including colon cancer, gastric cancer, lung cancer, prostate cancer, liver cancer, brea...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C331/24A61K31/26A61K9/00A61K36/00A61K48/00A61P35/00
Inventor 王龙贵乔仁伟程景才
Owner JC (WUXI) CO INC
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