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Nitrogen mustard-based flavonoid derivative, preparation method thereof and application in anti-tumor direction

A mustard-based flavonoid and derivative technology, applied in the field of medicinal chemistry, can solve the problems of low bioavailability, poor fat solubility and water solubility, etc.

Active Publication Date: 2019-02-26
BEIJING NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Although flavonoids have a wide range of physiological activities, they are all weak, and their fat solubility and water solubility are poor, and their bioavailability is low.

Method used

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  • Nitrogen mustard-based flavonoid derivative, preparation method thereof and application in anti-tumor direction
  • Nitrogen mustard-based flavonoid derivative, preparation method thereof and application in anti-tumor direction
  • Nitrogen mustard-based flavonoid derivative, preparation method thereof and application in anti-tumor direction

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preparation example Construction

[0040] The present invention also provides a preparation method of nitrogen-containing mustardyl flavonoid derivatives, comprising:

[0041] S1) reacting genistein or chrysin with a halogenated alkane represented by formula III under alkaline conditions to obtain compounds represented by formula IV and formula V;

[0042]

[0043] S2) reacting the compounds represented by formula IV and V with diethanolamine to obtain compounds represented by formula VI and VII;

[0044]

[0045] S3) reacting compounds represented by formulas VI and VII with thionyl chloride to obtain nitrogen-containing mustardyl flavonoid derivatives represented by formulas I and II;

[0046]

[0047] Wherein, X is a halogen; n is an integer greater than or equal to 0, preferably an integer of 1-3.

[0048] React genistein with the halogenated alkane represented by formula III under alkaline conditions; the molar ratio of the genistein to the halogenated alkane represented by formula III is prefera...

Embodiment 1

[0064] Target compound Ⅰ 1 preparation of

[0065] step 1:

[0066] Genistein (2.7g, 10mmol), anhydrous K 2 CO 3 (2.76g, 20mmol), 10mL of 1,2-dibromoethane and 150mL of acetone were added to a 250mL round bottom flask, heated and stirred at reflux for about 8h. Then stop the reaction, remove acetone by rotary evaporation, add petroleum ether to wash the obtained mixture to remove 1,2-dibromoethane, filter under reduced pressure, separate solid from liquid, and collect the solid. Wash with a large amount of distilled water to remove potassium carbonate, and dry. The crude product adopts the method purification of column chromatography (eluent consists of: CH 2 Cl 2 :CH 3 OH=60:1), the yellow solid 2a was finally obtained with a yield of 70%. 1 H NMR (400MHz, DMSO-D6) δ12.96(s, 1H), 9.58(s, 1H), 8.41(s, 1H), 7.38(d, J=8.6Hz, 2H), 6.82(d, J= 8.7Hz, 2H), 6.69(d, J=2.3Hz, 1H), 6.43(d, J=2.3Hz, 1H), 4.47–4.43(m, 2H), 3.86–3.78(m, 2H).

[0067] Step 2:

[0068] The above-p...

Embodiment 2

[0072] Target compound Ⅰ 2 preparation of

[0073] step 1:

[0074] Genistein (2.7g, 10mmol), anhydrous K 2 CO 3 (2.76g, 20mmol), 10mL 1,3-dibromopropane and 150mL acetone were added to a 250mL round bottom flask, and the rest of the steps were the same as step 1 in Example 1. A yellow solid 2b was obtained in 69% yield. 1 H NMR (600MHz, DMSO-D6) δ9.59(s, 1H), 8.41(s, 1H), 7.38(d, J=8.6Hz, 2H), 6.81(d, J=8.6Hz, 2H), 6.68 (d, J=2.2Hz, 1H), 6.42(d, J=2.2Hz, 1H), 4.20(t, J=6.0Hz, 2H), 3.66(t, J=6.6Hz, 2H), 2.26(p ,J=6.3Hz,2H).

[0075] Step 2:

[0076] The intermediate product 2b (0.391 g, 1 mmol) prepared above, diethanolamine (1.05 g, 10 mmol), and 50 mL of acetonitrile were added to a 100 mL round bottom flask, and the rest of the steps were the same as step 2 in Example 1. 3b was obtained as a pale yellow solid in 85% yield. 1 H NMR (600MHz, METHANOL-D4) δ8.09(s, 1H), 7.38(d, J=8.4Hz, 2H), 6.85(d, J=8.5Hz, 2H), 6.52(s, 1H), 6.35 (s,1H),4.14(t,J=6.0Hz,2H),3.62(t,J=5....

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Abstract

The invention discloses a preparation method of a class of nitrogen mustard-based flavonoid derivatives and application thereof in an anti-tumor activity study. As shown in the formula I and the formula II, n is an integer which is more than or equal to 0. Target compounds are not reported by literatures. The class of compounds can be used for inhibiting the growth activity of various tumor cells.An experiment shows that all the target compounds have better anti-tumor activity for tested seven cancer cells; compared with the existing anti-tumor drug 5-fluorouracil, the target compounds have higher growth inhibition activity for various tumor cells, wherein target compounds II 2 have the best anti-tumor effect, the IC50 value of the target compounds II 2 are all below 10muM for Hela, DU145, PC-3, MCF-7 and SH-SY5Y cells, and compared with an anti-tumor drug cis-platinum, the target compounds II 2 have the same order of magnitude. A further study discovers that the target compounds II 2can be used for inducing cell apoptosis by arresting the cycle of the Hela cells in a G2 / M phase, therefore, the target compounds II 2 are expected to be novel anti-tumor drugs.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and relates to a class of nitrogen-containing mustardyl flavonoid derivatives, a preparation method thereof and an application in anti-tumor cell proliferation. Background technique [0002] Flavonoids are a class of natural products that widely exist in legumes, and have been valued for their various physiological activities such as antitumor, antibacterial, antioxidative, antiosteoporotic, and estrogen-like. There are many kinds of flavonoids, which can be divided into isoflavones, flavonoids, flavonols, chalcones, anthocyanins, etc. according to the connection of the three carbon atoms in the middle of the compound and the relative position of the benzene ring. As an isoflavone with various biological activities, genistein exhibits weak estrogen-like effect and has certain inhibitory effect on the proliferation of estrogen-dependent tumor cells. Chrysin is a low-toxic natural flavonoid, whi...

Claims

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Application Information

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IPC IPC(8): C07D311/60C07D311/58A61K31/352A61P35/00
CPCA61P35/00C07D311/58C07D311/60
Inventor 延玺宋静磊彭静怡况婷瑞刘静
Owner BEIJING NORMAL UNIVERSITY
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