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Thiourea homologues epipodophyllotoxin compound and preparation method and application thereof

A technology of epipodophyllotoxin and compounds, applied in the fields of medicinal chemistry and pharmacology, can solve the problems of low selectivity and large side effects, and achieve the effect of simple preparation method, easy operation, and inhibitory activity of tumor cell growth

Inactive Publication Date: 2009-09-30
NANTONG UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The cytotoxic antitumor drugs currently used in clinical practice are not highly selective, resulting in relatively large side effects

Method used

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  • Thiourea homologues epipodophyllotoxin compound and preparation method and application thereof
  • Thiourea homologues epipodophyllotoxin compound and preparation method and application thereof
  • Thiourea homologues epipodophyllotoxin compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Example 1: Compound 2a: 4-[Benzoylthioureido]epipodophyllotoxin

[0028]

[0029] Add benzoyl isothiocyanate (195mg, 1.2mmol) to acetonitrile (20mL), add 4-aminoepipodophyllotoxin (413mg, 1mmol), reflux reaction for 4h, TLC detects that the reaction is complete, concentrate under reduced pressure, and use a silica gel column Chromatography (ethyl acetate:petroleum ether, 1:3) afforded 2a (446 mg, 77.5%) as a white solid.

[0030] R f 0.25 (ethyl acetate: petroleum ether, 1:3);

[0031] 1 H NMR (CDCl 3 ): δ2.00(s, 1H, 1-NH), 2.93(dd, J=4.8, 14.4, 1H, 2-H), 3.07(m, 1H, 3-H), 3.73(s, 6H, 3 ',5'-OCH 3 ), 3.78 (s, 3H, 4'-OCH 3 ), 3.80 (d, 1H, 4-H), 4.32 (m, 2H, 11-H), 4.62 (d, J=4.8, 1H, 1-H), 5.96 (s, 2H, -OCH 2 O), 6.28 (s, 2H, 2′, 6′-ArH), 6.52 (s, 1H, 8-ArH), 6.84 (s, 1H, 5-ArH), 7.48 (d, J=7.5, 1H, 3″-ArH), 7.51 (d, J=5.7, 1H, 5″-ArH), 7.62 (t, J=5.7, 1H, 4″-ArH), 7.79 (s, 1H, 2″-ArH), 7.81 (s, 1H, 6″-ArH), 10.67 (d, J=7.8, 1H, 2-NH);

[0032] 13 C NMR (C...

Embodiment 2

[0068] Drug Example 2: Cytotoxic Activity of Compound 2b on HepG-2 Cells

[0069] Cells in the logarithmic growth phase were inoculated on a 96-well plate, and drugs of different concentrations were added after 24 hours of adherence. Four parallel wells were set up for each concentration. After 68 hours of culture, MTT solution was added, and the culture was continued for 4 hours. The culture medium was discarded, and 150 μL of DMSO was added. Shake for 10min, measure the absorbance (A) value at 570nm with a microplate reader, and calculate the half inhibitory concentration (IC 50 ). IC of compound 2b 50 3.2×10 -5 M, while the IC of the positive control etoposide on HepG-2 cells 50 4.5×10 -4 M.

[0070] Experimental conclusions The thiourea epipodophyllotoxin with the structure shown in formula (1) has strong cytotoxic activity on HepG-2 cells, and may be developed into a new drug with anti-tumor effect.

Embodiment 3

[0071] Drug Example 3: Cytotoxic activity of compound 2c on Hela cells

[0072] Cells in the logarithmic growth phase were inoculated on a 96-well plate, and drugs of different concentrations were added after 24 hours of adherence. Four parallel wells were set up for each concentration. After 68 hours of culture, MTT solution was added, and the culture was continued for 4 hours. The culture medium was discarded, and 150 μL of DMSO was added. Shake for 10min, measure the absorbance (A) value at 570nm with a microplate reader, and calculate the half inhibitory concentration (IC 50 ). IC of compound 2-5 50 4.2×10 -5 M, while the IC of the positive control etoposide on Hela cells 50 5.0×10 -5 M.

[0073] Experimental conclusion The thiourea epipodophyllotoxin with the structure shown in formula (1) has strong cytotoxic activity on Hela cells, and may be developed into a new drug with antitumor effect.

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Abstract

The invention discloses a thiourea homologues epipodophyllotoxin compound and a preparation method and an application thereof, and the thiourea homologues epipodophyllotoxin compound is obtained in such a way that 4-amino epipodophyllotoxin and corresponding replaced benzoyl isorhodanic ester are put in acetonitrile solvent, toluene solvent or acetone solvent for reaction. The preparation method is simple and is easy to operate and the product has the function of inhibition of tumor cell growth activity.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry and pharmacology. Specifically, the present invention relates to thiourea epipodophyllotoxin compounds and preparation methods thereof and the effects of these derivatives on five tumor cell lines such as oral epithelial carcinoma cells (KB), human lung cancer cells (A549), human liver cancer cells (HepG2 ), human cervical cancer cells (Hela) and human breast cancer cells (MCF-7) were screened for tumor cell growth inhibitory activity. These derivatives are found to have a certain activity of inhibiting the growth of tumor cells, and can be expected to be used as antitumor drugs. Background technique [0002] With the advancement of medicine, general infectious diseases are gradually being controlled, and malignant tumor-cancer has become one of the main diseases that are common and seriously threaten human life and quality of life. The cytotoxic antitumor drugs currently used in cli...

Claims

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Application Information

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IPC IPC(8): C07D493/04A61K31/365A61P35/00
Inventor 赵育朱俐王丹陆亚鹏王成牛
Owner NANTONG UNIVERSITY
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