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Guidemycin and use thereof in tumor treatment

An anti-tumor drug, the technology of guidanamycin, which is applied in the field of geldanamycin derivatives, achieves the effects of high yield, clear molecular weight and structure, and high purity

Inactive Publication Date: 2012-11-21
MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] The geldanamycin derivative guidemycin (Guidemycin) and its anti-tumor effect involved in the present invention have not yet seen domestic and foreign related reports

Method used

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  • Guidemycin and use thereof in tumor treatment
  • Guidemycin and use thereof in tumor treatment
  • Guidemycin and use thereof in tumor treatment

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] : preparation of guidamicin

[0041] Dissolve geldanamycin (Sigma product) and hexamethylenediamine in chloroform, the molar ratio of the reactants is 1:10, stir and react at room temperature for 3 hours, extract the reaction solution with water after the reaction, discard the water layer, and keep the chloroform layer . The chloroform solution was blown dry with nitrogen to obtain compound 17-hexamethylenediaminogeldanamycin (compound A).

[0042] Dissolve compound A in DMF, add cinnamic acid at a molar ratio of 1:3, and simultaneously add DIPEA (N, N-Diisopropylethylamine) and HATU (O-(7-Azabenzotriazol-1-yl)- N, N, N', N'-tetramethyluronium hexafluorophosphate), stirred and reacted at room temperature for 12-24 hours to obtain the final product (1). The final product is purified by preparative thin-layer chromatography, and the developing conditions of the developing agent are chloroform: acetone=2: 1, and R f = Purple band at 0.5. The obtained silica gel powder ...

Embodiment 2

[0044] : Determination of the purity of guidamycin

[0045] Guidemycin purity testing equipment: Agilent 1100 high performance liquid chromatography, VWD detector, chromatographic column Kromasil C-18250×4.6mm 5 μm (Dima Company), workstation operating system Chemstation.

[0046] Chromatographic conditions: mobile phase: acetonitrile-water (0.1% TFA) solution (A: water, B: acetonitrile) flow rate: 1 mL / min.

[0047] Gradient elution conditions:

[0048] Time Solvent A(%) Solvent B(%) 0 90 10 10 10 90 14 10 90 15 90 10 20 90 10

[0049] Detection wavelength: 254nm,

[0050] Column temperature: 28°C,

[0051] Dissolve about 1 mg of guidenamycin sample in 3ml of mobile phase to obtain guidenamycin test solution. The injection volume is 5 μl. Using the area normalization method, the purity of guidenamycin is 95.06% ( image 3 ).

Embodiment 3

[0052] : Inhibitory effect of guidamycin on the growth of tumor cells cultured in vitro

[0053] MTT method was used to determine the inhibitory effect of guidamycin on the proliferation of human breast cancer cells MCF-7, human pancreatic cancer SW1990 cells, human liver cancer HepG2 cells, human lung cancer H460 cells, and human colorectal cancer HCT116 cells; Inhibitory effect of myelin on the proliferation of human myeloma U266 cells. The results of MTT and MTS / PMS showed that guidamicin had a significant inhibitory effect on the proliferation of tumor cells, and its IC 50 The values ​​are listed in Table 1 respectively.

[0054] Table 1 The inhibitory effect of guidamicin on the proliferation of different tumor cells

[0055]

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Abstract

The invention relates to a kueide mycin which is a novel derivative of geldanamycin. According to the anticancer activity experiment, kueide mycin has in both vitro and vivo antitumor activities. The kueide mycin has the in vitro activity characteristics of inhibiting tumor cell proliferation, inducing the tumor cell apoptosis, reducing related target proteins of Hsp 90 in the tumor cells, as well as inhibiting the tumor cell migration, and has in vivo antitumor activity characteristics of notably reducing poisonousness compared to the geldanamycin. The kueide mycin can obviously inhibit the growth of solid tumor of a nude mouse model of Human breast carcinoma xenografts after being injected in a peritoneal cavity and is expected to be developed into a clinical effective antitumor drug.

Description

Technical field: [0001] The present invention relates to a kind of geldanamycin derivative, in particular, relates to introducing the derivative guidemycin (Guidemycin) of cinnamic acid; in the application. Background technique: [0002] Heat shock protein 90 (heat shock proteins 90, Hsp90) is a high-abundance protein widely present in prokaryotes and eukaryotes. As a molecular chaperone, Hsp90's main function is to ensure the correct folding of its chaperone protein molecule, so that it maintains a normal biological conformation and then exerts biological activity. There are many kinds of these protein molecules, which play an important role in the process of cell growth, differentiation and survival. Proteins that have not been regulated by Hsp90 to form the correct active conformation are marked by ubiquitin and degraded by the ubiquitin-proteasome pathway. More importantly, many protein factors involved in tumor cell proliferation, apoptosis, and invasion also require...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D225/06A61K31/395A61P35/00
Inventor 李良娄志贤甄永苏
Owner MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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