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Amino-substituted staurosporin compound and preparation method and application thereof

A staurosporine and compound technology, applied in the field of amino-substituted staurosporine compounds and their preparation, can solve the problems of poor selectivity and achieve high inhibitory effect, high activity, and good application prospects

Active Publication Date: 2018-01-09
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

STA is a strong PKC inhibitor (IC 50 =2.7nM), mainly acting on various kinases, topoisomerases and cell cycle regulatory factors in the cell signal transduction pathway, but later proved to be a broad-spectrum kinase inhibitor with poor selectivity, so it could not be drugged

Method used

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  • Amino-substituted staurosporin compound and preparation method and application thereof
  • Amino-substituted staurosporin compound and preparation method and application thereof
  • Amino-substituted staurosporin compound and preparation method and application thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0037] 1. Seed solution

[0038] The above Streptomyces was inoculated into 500mL Erlenmeyer flasks containing 250mL of liquid medium, each bottle containing 250mL of Gaoshi No. 1 liquid medium, and cultured in a shaker at 28°C at 180rpm for 4 days to obtain seed liquid.

[0039] 2. Fermentation

[0040] Inoculate the above-mentioned seed liquid into the rice fermentation medium (made by the following weight components: rice 40g, 25% sea salt water 60mL) with the amount of inoculating 8mL per bottle, and stop the fermentation after 60 days of static culture at 28°C.

[0041] 3. Rough extraction

[0042] Soak each bottle of solid fermented product with about 200 mL of EA (ethyl acetate) overnight, filter through three layers of gauze to remove mycelia, collect the filtrate, and concentrate under reduced pressure to obtain a crude extract (oily extract).

[0043] 4. Separation and purification

[0044] The above crude extract was extracted three times with an equal volume of ...

Embodiment 2

[0047]The new compound obtained in the present invention is a white amorphous powder, and the high-resolution mass spectrum provides [M+H] at HRESIMS m / z 341.1381 + peak, suggesting a molecular weight of 340, combined with 1 H-NMR, 13 C-NMR and HSQC spectral data ( figure 1 , 2 and 3) the presumed molecular formula is C 21 h 16 N 4 O, the degree of unsaturation is 16. exist 1 The downfield region of H-NMR shows 8 aromatic proton signals δ H 9.26 (1H, d, J = 8.0Hz), 8.05 (1H, d, J = 7.8Hz), 7.82 (1H, d, J = 7.8Hz), 7.80 (1H, d, J = 7.8Hz), 7.55 ( 1H, brt), 7.42(1H, br t), 7.34(1H, br t), 7.22(1H, br t); three active hydrogen signals δ H 11.54 (1H, s), 8.47 (1H, s), 7.10 (1H, q, J = 5.5Hz); there is a methylene signal 4.95 (2H, s) and a methyl signal δ in the high field H 2.95 (3H, d, J=5.5Hz). Compared with the reported K252c, it is found that this compound has one more methyl group and one active hydrogen signal. further analysis 1 H- 1 H COZY and HMBC spectra ...

Embodiment 3

[0049] Proliferation inhibition experiment of human prostate cancer cell line PC3.

[0050] Cells in the logarithmic growth phase were taken and configured as 5×10 4 cells / mL, spread in 96-well culture plate at 100 μL / well, CO 2 Cultivate in the incubator for 24 hours, take out the culture plate, add different concentrations of samples to be tested in each well, set 3 duplicate holes for each concentration, and place in CO 2 After continuing to culture in the incubator for 72 hours, take out the culture plate, discard the culture medium, add 100 μL of 10% trichloroacetic acid (TCA) pre-cooled in a refrigerator at 4°C to each well to fix it, let it stand for 5 minutes, and then move the culture plate to 4 °C refrigerator overnight. Pour off the fixative, wash each well 5 times with deionized water, spin dry, and air dry. Add 70 μl of SRB solution to each well, place at room temperature for 20 minutes, remove the supernatant, wash 5 times with 1% acetic acid, and air dry. Th...

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PUM

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Abstract

The invention discloses an amino-substituted staurosporin compound and a preparation method and the application thereof. The amino-substituted staurosporin compound is characterized by being named as12-N-methyl-k252c and being shown as a structural formula I. The amino-substituted staurosporin compound is obtained from an actinomycete through separation and purification, and is authenticated to be the amino-substituted staurosporin compound named as 12-N-methyl-k252c; experimental detections find that the amino-substituted staurosporin compound has relatively high activity on prostate cancercells, and has a relatively high inhibitory effect on Brd4 protein; the amino-substituted staurosporin compound has a good application prospect in preparation of medicines for treating tumors, HIV, leukemia and other diseases.

Description

technical field [0001] The invention relates to the field of biotechnology, in particular to an amino-substituted staurosporine compound and its preparation method and application. Background technique [0002] Cancer is one of the major diseases that endanger human life and health, and has the characteristics of long disease course and high mortality. Prostate cancer is a malignant tumor commonly found in the male genitourinary system. Its incidence rate is the first among all male tumors in Western Europe and the United States, and its mortality rate is second only to lung cancer. Compared with western countries, the incidence of prostate cancer in my country is significantly lower, but in recent years due to the influence of various factors, it has shown a significant increase. The World Health Organization reported that in 2012, the number of cancer patients and deaths in the world continued to increase. Nearly half of the new cancer cases occurred in Asia, most of whic...

Claims

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Application Information

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IPC IPC(8): C07D487/14A61P29/00A61P35/00A61P35/02A61P31/18A61P17/00A61P19/02C12P17/10C12R1/465
Inventor 马忠俊周彪丁婉婧
Owner ZHEJIANG UNIV
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