CN106008481A - Flavonoid compound targeting tumor cells and preparation method of flavonoid compound - Google Patents
Flavonoid compound targeting tumor cells and preparation method of flavonoid compound Download PDFInfo
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- CN106008481A CN106008481A CN201610338291.4A CN201610338291A CN106008481A CN 106008481 A CN106008481 A CN 106008481A CN 201610338291 A CN201610338291 A CN 201610338291A CN 106008481 A CN106008481 A CN 106008481A
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Abstract
The invention belongs to the field of organic chemistry and relates to a flavonoid compound targeting tumor cells. A chemical structural formula of the flavonoid compound is as shown in a formula (I). Isoflavone and IR783 are reacted under the action of NaH to obtain the flavonoid compound after deprotection is performed under acidic conditions. The flavonoid compound has the advantage that a tumor cell growth inhibition effect is remarkably improved.
Description
Technical field
The present invention relates to heterocyclic compound thing, be specifically related to flavone compound.
Background technology
Since ancient times, because the impact of the active function of Chinese herbal medicine own early has been widely used for preventing generation and the treatment of different chronic disease, once had been reported that, and antitumor drug had more than 60% and derives from nature.According to National Cancer Institute (NCI) analysis of survey results, in the different plants and other natural extracts of the U.S., flavone compound is referred to as most important one group of natural anti-cancer compound.In the dietary structure in Asia, Semen sojae atricolor is one of which most important food ingredient, and it contains daidzein constituents.Numerous studies data show that flavone compound such as soybean isoflavone, such as 4', 5,7-trihydroxy-isoflavones, has the antitumor action of inside and outside, including breast carcinoma, carcinoma of prostate, hepatocarcinoma, colon cancer both at home and abroad.Genistein is once used for preventing protectively the mouse breast carcinoma of chemical induction, is embodied in generation and the variation reducing tumor, increases incubation period.Although the generation using substantial amounts of soy ration to can help to reduce breast carcinoma is observed in clinical experiment.
Flavone compound was primarily referred to as basic parent nucleus in the past is 2-phenyl chromone compounds, primarily now refers to the series compound that two phenyl ring (A ring and B ring) with phenolic hydroxyl group are connected with each other by central authorities' thricarbon atom.All there is, with a lot of laboratory animals and limited human experimentation, the problem that oral administration biaavailability is low in flavone compound, result shows that the oral administration biaavailability of this compounds is often even below 5% less than 10%.The aglycon dissolubility of flavone compound is the lowest, often less than 20g/ml in water, thus the bioavailability of medicine can be caused low.
Summary of the invention
The technical problem to be solved is to provide the flavone compound of a kind of targets neoplastic cells, and the effect of this flavone compound suppression growth of tumour cell significantly improves.
The present invention solves the technical scheme of the problems referred to above:
A kind of flavone compound of targets neoplastic cells, its structure is for shown in chemistry formula I:
Flavone compound of the present invention uses method commonly used in the art synthesis; as; by the isoflavone shown in (II) formula, under NaH effect and IR783 reaction obtains compound shown in (III) formula, then compound deprotection shown in (III) formula is obtained the flavone compound shown in (I) formula.
The concrete grammar that the present inventor is recommended comprises the steps of:
(1) by the 4' of 1 molar part, 5,7-trihydroxy-isoflavones, the potassium hydroxide of 1 molar part and the potassium iodide of 0.01 molar part add in DMF, be slowly added to the chloromethyl methyl ether of 1.2 molar part, stir 12 hours under room temperature；The reactant liquor that obtain is added in deionized water, and adjusts solution for acidity, be filtrated to get white solid；The white solid recrystallization in ethanol that will obtain, obtains the isoflavone shown in lower formula II,
(2) isoflavone shown in 1 molar part (II) formula and appropriate dry DMF mix homogeneously are taken；It is slowly added to 4 molar part NaH, stirs 15 minutes at 0 DEG C；Add 1 molar part IR783, room temperature reaction 18h；Ether extracts, and ether extraction liquid is dried to obtain crude product；Crude product is washed and is dried to obtain compound shown in lower formula III,
(3) take compound and proper amount of methanol mix homogeneously shown in 1 molar part (III) formula, add hydrochloric acid and adjust PH to 0～1.0 deprotection group MOM, 4h is stirred at room temperature；Filter, after filtering residue washing, be dried to obtain crude product；Crude product crosses silica column purification, obtains the flavone compound shown in formula I.
The concrete reaction scheme of above-mentioned synthetic method is as follows:
In said method, the isoflavone shown in (II) formula can be according to document (Qiang Xiaoming, Yuan Wen, Sang Zhipei, Deng Yong, the synthesis of genistein carbamate derivates and bioactivity research, organic chemistry, 2013,33:621-629) prepared by described method.
By 4', 5, the chemical constitution of 7-trihydroxy-isoflavone understands, its 4' and 7 is positioned at and is easier to be connected with IR783, and the present invention specifically selects IR783 and 4', and 5,4 ' position hydroxyls of 7-trihydroxy-isoflavone connect, the most relatively prior art has the advantages that the most both have antineoplastic activity and targets neoplastic cells effectiveness, and substantially increases the water solublity of compound, and then significantly improves the effect of its suppression growth of tumour cell.
Accompanying drawing explanation
Fig. 1 is flavone compound of the present invention and synthesizes its two kinds of raw materials curve to breast cancer cell inhibitory activity.
Fig. 2 is 10% and under 25% two kind of drug level, flavone compound of the present invention and synthesize its two kinds of raw materials to breast cancer cell suppression live bar diagram.
Fig. 3 is flavone compound of the present invention and synthesizes its two kinds of raw materials curve to normal breast cell virulence.
Fig. 4 is 25% and under 50% two kind of drug level, flavone compound of the present invention and synthesize its two kinds of raw materials bar diagram to normal breast cell virulence.
Detailed description of the invention
Embodiment one (preparing flavone compound)
1. the synthesis of the isoflavone shown in (II) formula
According to document (Qiang Xiaoming, Yuan Wen, Sang Zhipei, Deng Yong, the synthesis of genistein carbamate derivates and bioactivity research, organic chemistry, 2013,33:621-629) method disclosed in, 4' is added in reaction bulb, 5,7-trihydroxy-isoflavones (5.0g, 18.5mmol), KOH (1.1g, 18.5mmol), potassium iodide (0.3g, 1.85mmol) and N, dinethylformamide (40mL), it is added dropwise to chloromethyl methyl ether (1.68mL, 22.2mmol) after reaction being stirred at room temperature 1 hour, continues reaction 12h is stirred at room temperature.After reaction terminates, reactant liquor is poured in deionized water (120mL), it is that 10%HCl aqueous solution regulation pH value of solution is to acid with mass fraction, filter the off-white color solid crude product separated out, gained crude product, through ethyl alcohol recrystallization, obtains the isoflavone (see summary of the invention) shown in (II) formula.
2. the synthesis of compound shown in (III) formula
The isoflavone shown in (II) formula taking 2mmol is dissolved in the dry DMF of 3ml, it is slowly added to the NaH of 8mmol, add, after stirring 15 minutes at 0 DEG C, the 2mmol IR783 being dissolved in 1:1DMF:MeOH (40mL), after reacting 18 hours under room temperature, add ether to extract three times, merge ether extraction liquid and be dried to obtain crude product.It is dried to obtain dark green solid 1.73g, productivity 85% after being washed by crude product.
According to a conventional method dark green solid obtained above has been carried out mass spectrum, hydrogen nuclear magnetic resonance analysis of spectrum.Result is as follows:
Mass spectrum (MALDI-TOF) is [m/z 1026 (M+)]
1H NMR(500MHz,CD3OD)δppm:1.38(s,12H,CH3X 4), 1.75-2.11 (m, 10H), 2.79 (t, J=5.0Hz, 4H, CH2), 2.88 (t, J=5.0Hz, 4H, CH2),3.48(s,3H,OCH3), 4.15 (t, J=5.0Hz, 4H, CH2x 2),5.27(s,2H,CH2), 6.22 (d, J=15.0Hz, 2H, ArH), 6.45 (s, 1H, CH), 6.63 (s, 1H, CH), 7.20 (m, 4H, ArH), 7.30 (d, J=10.0Hz, 2H, ArH), 7.37 (m, 4H, ArH) 7.64 (d, J=10.0Hz, 2H, ArH), 8.01 (d, J=15.0Hz, 2H ,=CH), 8.18 (s, 1H, ArH) 8.38 (s, 1H, exchangeable OH)
From above-mentioned qualification result, gained solid is compound shown in (III) formula, and its structural formula isThe productivity being computed method described in this example is 85%.
3. the synthesis of the flavone compound shown in (I) formula.
By compound dissolution shown in 1.0mmol (III) formula in 40ml methanol, add HCl and adjust PH to 1.0 to deprotect group MOM, after reacting 4 hours under room temperature, filter, after the washing of filtering residue water, be dried to obtain crude product.Crude product crosses silica column purification, with the acetonitrile that volume ratio is 1:1 with methanol mixed solution as cleaning mixture, collects green wash liquid, is dried to obtain dark green solid 393mg, is computed the productivity 41% of method described in this example.
According to a conventional method above-mentioned dark green solid has been carried out mass spectrum, hydrogen nuclear magnetic resonance analysis of spectrum.Result is as follows:
Mass spectrum (MALDI-TOF) is [m/z 959 (M-)]
1H NMR(500MHz,dmso-d6)δppm:1.29(s,12H,CH3x 4),1.75-2.22(m,10H),1.94(m,4H,CH2), 2.74 (t, J=5.0Hz, 4H, CH2), 4.13 (t, J=5.0Hz, 4H, CH2X 2), 6.22 (d, J=15.0Hz, 2H, ArH), 6.38 (s, 1H, CH), 6.63 (s, 1H, CH), 7.18 (m, 4H, ArH), 7.24 (d, J=10.0Hz, 2H, ArH), 7.35 (m, 4H, ArH) 7.48 (d, J=10.0Hz, 2H, ArH), 7.81 (d, J=10.0Hz, 2H, ArH), 7.83 (brd, J=10.0Hz, 2H,=CH), 8.18 (s, 1H, ArH) 8.36 (s, 1H, exchangeable OH).
From above-mentioned qualification result, gained solid is compound shown in (I) formula, and its structural formula is
Embodiment two (effect experimental)
In following experiment, flavone compound of the present invention used is compound shown in (I) formula.
(1) solubility experiment of flavone compound of the present invention
Weighing 0.8mg 4', 5,7-trihydroxy-isoflavones, be dissolved in 500 μ L n-octyl alcohols, supersound process treats after 5 minutes that its solution becomes clarification and is added thereto to the water of 500 μ L again；Weigh 2.78mg flavone compound of the present invention, be dissolved in 500 μ L water, after its solution becomes clarification, be added thereto to the n-octyl alcohol of 500 μ L again.Both the above solution is centrifuged 5 minutes (Fisher Scientific Eppendorf MiniSpin) with the rotating speed of 4000 turns, the water layer of the n-octyl alcohol layer and 50 μ L that take 50 μ L again from both the above solution respectively joins in the DMSO of 200 μ L, parallel take three times, be placed in 96 orifice plates.Take 50 μ L n-octyl alcohols and 50 μ L water are added separately in 200 μ LDMSO be configured to blank group, under the conditions of 280nm, detect UV absorption value by microplate reader (Molecular Devices Spectra MAX 190).By detection UV absorption value, calculating 4', the log P value of 5,7-trihydroxy-isoflavones and flavone compound of the present invention is respectively 0.76 and-0.92.
Test method determination is surveyed by version Pharmacopoeia of the People's Republic of China note on the use dissolubility in 2015, under the conditions of 25 DEG C ± 2 DEG C, every strength shaking in 5 minutes 30 seconds, within 30 minutes, observe dissolving situation, during such as invisible particles of solute, i.e. think and be completely dissolved, found that 4', 5,7-trihydroxy-isoflavones limit meltage in the water of 100ml is 0.297mg；The flavone compound of the present invention limit meltage in the water of 100ml is 0.1179g.Visible, the dissolubility of flavone compound of the present invention is 4', 422.58 times of 5,7-trihydroxy-isoflavones.
(2) the flavone compound of the present invention inhibitory action to human breast cancer cell MCF 7
By human breast cancer cell MCF 7 cell suspension inoculation (every hole 2.6 × 10 in 12 orifice plates4Individual cell), draw culture fluid, it is separately added into following three kinds of compounds IR783,4', 5, compound solution shown in 7-trihydroxy-isoflavone and chemistry formula I, it is 5 μMs, 10 μMs, 25 μMs, 50 μMs, 75 μMs that concentration is respectively every hole compound concentration, two orifice plates of the parallel setting of each concentration.
By above-mentioned 12 orifice plates at 5%CO2, hatch 72 hours at 37 DEG C after, culture fluid adds the HEPES-MgCl of 1ml after rinsing twice2Buffer vibrates 15 minutes, adds ZAP 0.1ml and vibrates 10 minutes, takes out in the Isoton that 1ml adds 9ml, count nucleus with cell counter, count nucleus with cell counter in each orifice plate.To show the compound impact (see Fig. 1 and 2) on human breast cancer cell MCF 7 shown in chemistry formula I.
Result shows compound, 4' shown in (I) formula, and 5,7-trihydroxy-isoflavones compare with IR 783, and MCF7 breast cancer cell is had obvious inhibitory action.
(3) the flavone compound of the present invention effect to people normal breast cell MCF 10A
People normal breast cell MCF 10A is seeded in 12 orifice plates, every hole inoculating cell 2.6 × 104Individual, add the DMEM/F12 culture medium containing 5%Horse serum, at 5%CO2, hatch 48 hours at 37 DEG C, wait that cell attachment grows into 50-70%, draw culture fluid, it is separately added into following three kinds of compounds IR783,4', 5, compound solution shown in 7-trihydroxy-isoflavone and chemistry formula I, it is 5 μMs, 10 μMs, 25 μMs, 50 μMs, 75 μMs that concentration is respectively every hole compound concentration, two orifice plates of the parallel setting of each concentration.
By above-mentioned 12 orifice plates at 5%CO2, hatch 72 hours at 37 DEG C after, culture fluid adds the HEPES-MgCl of 1ml after rinsing twice2Buffer vibrates 15 minutes, add ZAP 0.1ml to vibrate 10 minutes, each orifice plate takes out in the Isoton that 1ml adds 9ml, with cell counter, nucleus is counted, to show the impact (see Fig. 3 and 4) on human breast cancer cell MCF 7 of the compound shown in (I) formula.
Result shows that compound shown in (I) formula compares with IR 783, has obvious inhibitory action to human tumor cells MCF 7, and inconspicuous to the inhibitory action of people normal breast cell MCF 10A.
Claims (2)
1. a flavone compound for targets neoplastic cells, its structure is for shown in chemistry formula I:
2. the method preparing flavone compound described in claim 1, the method comprises the steps of,
(1) by the 4' of 1 molar part, 5,7-trihydroxy-isoflavones, the potassium hydroxide of 1 molar part and the potassium iodide of 0.01 molar part add
Enter in DMF, under room temperature, be slowly added to the chloromethyl methyl ether of 1.2 molar part, stir 12 hours；The reactant liquor obtained is added
In deionized water, and adjust solution for acidity, be filtrated to get white solid；The white solid recrystallization in ethanol that will obtain,
Obtain the isoflavone shown in lower formula II,
(2) isoflavone shown in 1 molar part (II) formula and appropriate dry DMF mix homogeneously are taken；It is slowly added to 4 molar part
NaH, stirs 15 minutes at 0 DEG C；Add 1 molar part IR783, room temperature reaction 18h；Ether extracts, and ether extraction liquid is dried
Obtain crude product；Crude product is washed and is dried to obtain compound shown in lower formula III,
(3) take compound and proper amount of methanol mix homogeneously shown in 1 molar part (III) formula, add hydrochloric acid and adjust PH to 0～1.0 to go
Blocking group MOM, is stirred at room temperature 4h；Filter, after filtering residue washing, be dried to obtain crude product；Crude product crosses silica column purification,
Obtain the flavone compound shown in formula I.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108727245A (en) * | 2018-07-02 | 2018-11-02 | 广州中医药大学(广州中医药研究院) | A kind of salicylic acid compounds and its preparation method and application |
| CN109796444A (en) * | 2019-04-02 | 2019-05-24 | 中国药科大学 | A kind of Near-infrared Double fluorescent probe compounds and preparation method and application |
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| EP0670374A1 (en) * | 1994-03-01 | 1995-09-06 | Li-Cor, Inc. | A method of identifying strands of DNA using infrared fluorescent labels |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108727245A (en) * | 2018-07-02 | 2018-11-02 | 广州中医药大学(广州中医药研究院) | A kind of salicylic acid compounds and its preparation method and application |
| CN108727245B (en) * | 2018-07-02 | 2021-09-28 | 广州中医药大学(广州中医药研究院) | Salicylic acid compound and preparation method and application thereof |
| CN109796444A (en) * | 2019-04-02 | 2019-05-24 | 中国药科大学 | A kind of Near-infrared Double fluorescent probe compounds and preparation method and application |
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Application publication date: 20161012 |