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Novel multifunctional podophyllotoxin derivate as well as preparation method and application thereof

A podophyllotoxin, multifunctional technology, applied in the field of new multifunctional podophyllotoxin derivatives and its preparation, to achieve the effects of inhibiting angiogenesis, inhibiting cancer cell metastasis, and excellent biological activity

Active Publication Date: 2017-12-26
河南普诺易生物制品研究院有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although many podophyllotoxin derivatives have been prepared[12-19], the new derivatives prepared by the present invention have not been reported yet, and the drug exhibits excellent anti-invasion and metastasis, anti-angiogenesis and anti-liver cancer activities

Method used

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  • Novel multifunctional podophyllotoxin derivate as well as preparation method and application thereof
  • Novel multifunctional podophyllotoxin derivate as well as preparation method and application thereof
  • Novel multifunctional podophyllotoxin derivate as well as preparation method and application thereof

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Embodiment 1

[0045] The preparation method of novel multifunctional podophyllin derivatives of the present invention, its specific synthetic route is:

[0046]

[0047] This embodiment takes the synthesis of pyridine aldehyde hydrazone dithioformate propionate podophyllotoxin ester as an example

[0048] 1. Reagents

[0049] Absolute ethanol (Tianjin Deen Chemical Reagent Co., Ltd.), bromopropionic acid (Sarn Chemical Technology (Shanghai) Co., Ltd.), KOH (Tianjin Deen Chemical Reagent Co., Ltd.), 80% hydrazine hydrate (Tianjin Tianli Chemical Reagent Co., Ltd.), carbon disulfide (Tianjin Tianli Chemical Reagent Co., Ltd.), 2-pyridinaldehyde (Sigma), 4-desmethylpodophyllotoxin (Shanghai Fusheng Industrial Co., Ltd.).

[0050] 2. Synthesis of 2-pyridine aldehyde hydrazone dithioformate propionate podophyllotoxin ester

[0051] The synthesis of compound III refers to the patent method of our research group (patent application number is 201610650310.7), that is, take 1 mmol of KOH (56.1 ...

Embodiment 2

[0054]Inhibitory effect on DNA topoisomerase (take 2-pyridylhydrazone dithioformate propionate as an example)

[0055] 1. Reagents and testing instruments

[0056] BSA, glycerol, ATP, EDTA, SDS, TrisHCl, EB (Sigma). Bromophenol blue, boric acid, agarose, Tocan360 gel scanner (Shanghai Tiancheng Technology Co., Ltd.).

[0057] 2. Method

[0058] The cell nucleus extract was prepared according to the literature method [Fu Y, Yang Y, Zhou S, Liu Y et al., Ciprofloxacin containing Mannich base and its copper complex induce antitumor activity via different mechanism of action. Int J Oncol.2014; 45:2092-2100 .]. Add 0.4 μg of nuclear extract to topoisomerase evaluation solution (10 mM Tris-HCl (pH=7.5), 1 mM EDTA, 1 mM ATP, 150 mM NaCl, 0.1% BSA (Bovine serum albumin) and 5% glycerol), and then Add 1 μL, 2 μL or 3 μL of test substance (1 mM in 8% DMSO), finally add 0.4 μg pUC18 and make the total volume 20 μL, incubate in a water bath at 37°C for 30 min, add 5 μL of stop solution...

Embodiment 3

[0060] Inhibitory Effect of Podophyllotoxin Propionate 2-Pyridylhydrazone Dithiocarbamate on Matrix Metalloproteinases

[0061] 1. Reagents and testing instruments

[0062] BSA, glycerol, ATP, EDTA, SDS, TrisHCl, EB (Sigma), bromophenol blue, boric acid, agarose, Tocan360 gel scanner (Shanghai Tiancheng Technology Co., Ltd.).

[0063] 2. Method

[0064] Gelatin zymogram according to literature method [Pan X, Han H, Wang L, Yang L, Li R, Li Z, Liu J, Zhao Q, Qian M, Liu M, Du B. Nitidine Chloride inhibits breast cancer cells migration and invasion by suppressing c-Src / FAK associated signaling pathway. Cancer Lett. 2011;313:181-191.]. Briefly, HCCLM3 cells were cultured in serum-free medium, one without drug (control), and the others were added with 0.75 μM and 1.5 μM drugs respectively, cultured for 12 hours, collected the supernatant, and centrifuged, and the supernatant was quantified to obtain the protein concentration . Then the same amount of protein (30 μg) was added ...

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Abstract

The invention discloses a novel multifunctional podophyllotoxin derivate as well as a preparation method and application thereof, and belongs to the technical field of anti-tumor active compound synthesis. The invention is characterized in that the novel multifunctional podophyllotoxin derivate has a structural formula which is shown in the description, wherein n is equal to 0 to 8. The invention also discloses the preparation method of the novel multifunctional podophyllotoxin derivative and the application of the derivative in the preparation of antitumor drugs. A kind of bifunctional inhibitor which not only can inhibit the topoisomerase of tumor cells but also can inhibit matrix metalloproteinase in microenvironment is prepared, and has excellent biological activity: (1) inhibiting liver cancer and colon cancer cell growth in vitro and in vivo; (2) inhibiting angiogenesis and inhibiting cancer cell metastasis in a very low concentration; (3) inhibiting DNA topoisomerase and matrix metalloproteinase.

Description

technical field [0001] The invention belongs to the technical field of synthesis of antitumor active compounds, and specifically relates to a novel multifunctional podophyllotoxin derivative and its preparation method and application. Background technique [0002] Tumor is one of the major diseases that threaten human life [1-2]. In recent years, great progress has been made in the study of tumors, but for malignant tumors, there is a lack of effective means to control them clinically [3]. Finding effective, highly selective, and low-toxic antitumor drugs is still an important topic in current medical research. With the in-depth understanding of tumors, drug research based on tumor molecular mechanisms has also made some progress [4]. Traditionally, the research and development of chemotherapy drugs mainly revolves around the direct effect of drugs on solid tumors. Most of these drugs obtain effective active ingredients from natural products, and then undergo structural mo...

Claims

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Application Information

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IPC IPC(8): C07D493/04A61P35/00
CPCC07D493/04
Inventor 李长正黄腾飞康丽霞付云李翠萍王婷婷孙颜杰
Owner 河南普诺易生物制品研究院有限公司
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