CN105541676A - 2-butyl sulfoxide-1,4-naphthoquinone compound - Google Patents
2-butyl sulfoxide-1,4-naphthoquinone compound Download PDFInfo
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- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/02—Preparation of sulfones; Preparation of sulfoxides by formation of sulfone or sulfoxide groups by oxidation of sulfides, or by formation of sulfone groups by oxidation of sulfoxides
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Abstract
The invention discloses a kind of 2- fourth sulfoxide -1,4-naphthoquinone compounds, solve the less problem of the research of 5,8 1,4-naphthoquinones without containing any substituent group. The structural formula of the compound are as follows:
. 2- fourth sulfoxide -1,4-naphthoquinone compound provided by the invention, the 5 of the compound, 8 do not contain any substituent group, and 2 are replaced by sulfydryl, and 2 sulphur are oxidized to sulfoxide, so that naphthoquinone compound has more superior anticancer activity.
Description
Technical field
The present invention relates to a kind of new compound.
Background technology
Traditional new drug development approach is developed using effective components from natural materials as lead compound and is studied new drug.Asian puccoon is that medicinal history is long, pharmacological action traditional Chinese medicine widely, and its main pharmacodynamics composition Shikonin is the lead compound very with development potentiality.Shikonin is that the naphthoquinone compound of representative has anti-inflammatory, antibacterial, antiviral, anti-malarial, the multiple physiologically active such as antitumor.Particularly in anticancer research, reported that it has inhibition tumor cell growth, cell death inducing, suppresses DNA topoisomerase, arrestin Tyrosylprotein kinase, the multiple mechanism of action such as angiogenesis inhibitor.Therefore, naphthoquinones class is the interested compounds of Many researchers always.
Research in recent years for naphthoquinone compound mainly concentrates on 2 replacements or 65,8-dihydroxyl 1,4-naphthoquinones and 5,8-dimethoxy 1,4-naphthoquinone replaced, and fewer to 5,8 researchs not containing any substituent 1,4-naphthoquinone.
Previous research report display: the naphthaquinone derivatives of 2 sulfydryl replacements has good antitumour activity.And the antitumour activity that in the naphthaquinone derivatives of 2 sulfydryl replacements, the compound of sulfoxide series is more superior than the display of unoxidized sulfydryl series.Therefore research and design 5,8 not containing substituting group, and the naphthaquinone derivatives that 2 sulphur is oxidized to sulfoxide is necessary.
Summary of the invention
In order to solve the problem in background technology, the invention provides a kind of new compound, 2-fourth sulfoxide-1,4-naphthoquinone.
In order to realize foregoing invention object, the technical solution used in the present invention is: a kind of 2-fourth sulfoxide-1,4-naphthoquinone compound,
It is characterized in that the structural formula of this compound is:
.
The preparation method of above-mentioned 2-fourth sulfoxide-1,4-naphthoquinone compound is:
(1) synthesis of 2-fourth sulfydryl-1,4-naphthoquinone
In reaction vessel, add 1,4-naphthoquinone and methyl alcohol, the amount of methyl alcohol meets fully dissolves 1,4-naphthoquinones, the two adds 1-butyl sulfhydryl after mixing, 1-butyl sulfhydryl and 1, the mol ratio of 4-naphthoquinones is 1.5:1, after reacting 3-5 hour under room temperature, in reaction vessel, add sodium dichromate 99 and the vitriol oil, sodium dichromate 99 and 1, the mol ratio of 4-naphthoquinones is 1:5, the mol ratio of the vitriol oil and 1,4-naphthoquinone is 3:4, continues reaction 5-10 minute; Then with methylene dichloride and saturated aqueous common salt extraction, anhydrous sodium sulfate drying, filters, is concentrated into drying, obtains 2-fourth sulfydryl-1,4-naphthoquinone;
(2) synthesis of 2-fourth sulfoxide-1,4-naphthoquinone
In reaction flask, add step (1) product 2-fourth sulfydryl-1,4-naphthoquinones and chloroform, the amount of chloroform meets fully dissolves 2-fourth sulfydryl-1,4-naphthoquinone, continues to add 3-chloroperoxybenzoic acid, 3-chloroperoxybenzoic acid and 2-fourth sulfydryl-1, the mol ratio of 4-naphthoquinones is 1.2:1, reacts 1.5-2.5 hour, add 5%NaHCO after reacting completely at 0 DEG C of temperature
3termination reaction after 3-chloroperoxybenzoic acid superfluous in solution neutralization reaction; Reaction product is through methylene dichloride and saturated aqueous common salt extraction, and anhydrous sodium sulfate drying, filters, be concentrated into drying, obtain 2-fourth sulfoxide-1,4-naphthoquinone.
Beneficial effect of the present invention: the invention provides a kind of new 2-fourth sulfoxide-1,4-naphthoquinone compound, 5 of this compound, 8 containing any substituting group, and 2 are replaced by sulfydryl, and 2 sulphur are oxidized to sulfoxide, make naphthoquinone compound have more superior antitumour activity.
Accompanying drawing explanation
Fig. 1 is the lethal effect of BSNQ to Hep3B cells cell.
Fig. 2 is the lethal effect of BSNQ to human hepatoma HepG2 cell.
Fig. 3 is the lethal effect of BSNQ to people liver cancer Huh7 cell.
Fig. 4 A is with after BSNQ process Hep3B cell, utilizes fluorescence microscope apoptosis situation map.
Fig. 4 B is the quantitative analysis figure of Fig. 4 A.
Fig. 5 A is with after BSNQ process Hep3B cell, utilizes Apoptosis by Flow Cytometry situation map.
Fig. 5 B is the quantitative analysis figure of Fig. 5 A.
Fig. 6 A is with after BSNQ process HepG2 cell, utilizes fluorescence microscope apoptosis situation map.
Fig. 6 B is the quantitative analysis figure of Fig. 6 A.
Fig. 7 A is with after BSNQ process Huh7 cell, utilizes fluorescence microscope apoptosis situation map.
Fig. 7 B is the quantitative analysis figure of Fig. 7 A.
Embodiment
Below in conjunction with accompanying drawing and specific embodiment, the present invention is described further:
Embodiment: the preparation of 2-fourth sulfoxide-1,4-naphthoquinone
(1) synthesis of 2-fourth sulfydryl-1,4-naphthoquinone
In 100ml reaction flask, add 1,4-naphthoquinones 158.15mg (1mmol) and methyl alcohol 30ml, 1-butyl sulfhydryl 166 μ l (1.5mmol) is added after mixing, react under room temperature after 4 hours, in mixture, add sodium dichromate 99 59.6mg (0.2mmol) and the vitriol oil 40.8 μ l (0.75mmol), react after 5-10 minute and terminate.Through methylene dichloride and saturated aqueous common salt extraction, appropriate anhydrous sodium sulfate drying, filters, is concentrated into drying, obtains crude product, through TLC preparation, obtains 2-fourth sulfydryl-1,4-naphthoquinone.
(2) synthesis (BSNQ) of 2-fourth sulfoxide-1,4-naphthoquinone
In 50ml reaction flask, add above-mentioned product 2-fourth sulfydryl-1,4-naphthoquinone 246.32mg (1mmol) and chloroform 20ml, slowly add 3-chloroperoxybenzoic acid (MCPBA) 276.1mg (1.2mmol), react two hours at 0 DEG C of temperature, after reacting completely, add 5%NaHCO
3solution, termination reaction.Through methylene dichloride and saturated aqueous common salt extraction, anhydrous sodium sulfate drying, filters, is concentrated into drying, obtains crude product, through TLC preparation, obtains 2-fourth sulfoxide-1,4-naphthoquinone.
Experimental example
One, BSNQ is to the lethal effect of cancer cells
Experimental technique: (MTT experiment)
1. inoculating cell: be made into individual cells suspension with the nutrient solution containing 10% tire calf serum, be inoculated into 96 orifice plates with 10000, every hole cell, every pore volume is 200 μ l;
2. culturing cell: 5%CO
2, hatch 24h for 37 DEG C, be paved with at the bottom of hole to cell monolayer;
3. serum starvation: dosing 2h changed nutrient solution (nutrient solution containing 1%FBS) in the past;
4. drug treating: the BSNQ prepared being got respectively final concentration is 0,1,3,10,20,30,40,50,60,70,80,100 μMs of process Hep3B cells, HepG2 and Huh7 cell 24h;
5. color reaction: every hole adds MTT solution (5mg/ml prepares with PBS, pH7.4) 20 μ l.After continuing to hatch 2-4h, careful suction abandons culture supernatant in hole, carefully washs 2 times with PBS, and then every hole adds 100 μ l dimethyl sulfoxide (DMSO) (DMSO), shakes 10 minutes, crystallization is fully dissolved;
6. colorimetric: select 490nm wavelength, enzyme-linked immunosorbent assay instrument measures each hole absorbance value, record result take time as X-coordinate, and light absorption value is that ordinate zou draws Growth of Cells histogram, the results are shown in Figure 1-Fig. 3 and table 1.
Interpretation of result:
BSNQ(IC can be found out in Fig. 1-Fig. 3
50: 1.40 μMs) to Hep3B cells, HepG2 and Huh7, all there is good kill capability, it kills and wounds the increase of intensity drug level and raises gradually.
As can be seen from following table 1 also, BSNQ(IC
50: 1.40 μMs) to Hep3B cells, HepG2 and Huh7, all there is good kill capability, it kills and wounds the increase of intensity drug level and raises gradually.
Table 1BSNQ is to the IC of human liver cancer cell lethal effect
50value
Two, BSNQ is to the apoptotic effect of cancer cells
Experimental technique: (experiment in vitro-Annexin-V staining)
1. inoculating cell: be made into individual cells suspension with the nutrient solution containing 10% tire calf serum, be inoculated into 12 orifice plates with 10,000, every hole cell, every pore volume is 1ml;
2. culturing cell: 5%CO2, hatches 24h for 37 DEG C, is paved with at the bottom of hole to cell monolayer;
3. drug treating: add the BSNQ(IC prepared
50: 1.40 μMs), process different time (0,3,6,12,24h);
4. wash 2 times with PBS, add 195 μ lAnnexinV-FITC in conjunction with liquid, then add 5 μ lAnnexinV-FITC and mix gently;
5. add 10 μ l propidium iodide (PropidiumIodide, PI) staining fluids, mix gently;
6. room temperature (20-25 DEG C) lucifuge hatches 15 minutes;
7. (A) form of observation of cell and change of color under fluorescent microscope, green fluorescence is AnnexinV-FITC staining positive cells, and red fluorescence is propidium iodide positive cells.Only dyeed by green fluorescence, and the cell of small volume is apoptotic cell; By red or green and redness is two contaminates, and the larger cell of volume is non-viable non-apoptotic cell; The cell be not colored is normal cell.Random observation 200 cells, try to achieve the per-cent shared by various cell, and each sample counting is averaged for 3 times;
(B) Flow Cytometry methods simultaneously, is also utilized to detect BSNQ to the apoptosis of human liver cancer cell.
1, with BSNQ process Hep3B cell, BSNQ is detected to the apoptosis of Hep3B cells cell
Adopt above-mentioned experimental technique, the experimental result obtained is shown in Fig. 4 A, Fig. 4 B, Fig. 5 A and Fig. 5 B, and wherein Fig. 4 A is with after BSNQ process Hep3B cell, and utilize fluorescence microscope apoptosis situation map, shikonin and 5-FU is positive controls; Fig. 4 B is the quantitative analysis figure of Fig. 4 A.Fig. 5 A is with after BSNQ process Hep3B cell, utilizes Apoptosis by Flow Cytometry situation map; Fig. 5 B is the quantitative analysis figure of Fig. 5 A.
Interpretation of result
Be 1.40 μMs with BSNQ(final concentration) process Hep3B cells cell 0,3,6,12, after 24h, carry out the two dye experiment of AnnexinV-FITC/PI, and at fluorescence microscope.As can be seen from Fig. 4 B, along with the continuous increase of drug exposure times, AnnexinV-FITC fluorescence intensity also strengthens gradually, and its apoptosis degree also significantly increases.Especially, when the time is 24h, the fluorescence intensity of cell is the highest.Result illustrates, BSNQ effectively can induce the apoptosis of Hep3B cell, and in time-dependent manner.
Be 1.40 μMs with BSNQ(final concentration) process Hep3B cells cell 0,3,6,12, after 24h, carry out AnnexinV-FITC and PI and mark, by Apoptosis by Flow Cytometry situation.As can be seen from Fig. 5 B, along with the continuous increase of drug exposure times, the apoptotic degree of liver cancer Hep3B also increases thereupon, and especially when drug exposure times reaches 24h, the level of apoptosis of cell obviously increases.The result shows, BSNQ effectively can induce the apoptosis of Hep3B, and in time-dependent manner.
2, with BSNQ process HepG2 cell, BSNQ is detected to the apoptosis of human hepatoma HepG2 cell
Adopt above-mentioned experimental technique, the experimental result obtained is shown in Fig. 6 A and Fig. 6 B, and wherein Fig. 6 A is with after BSNQ process HepG2 cell, and utilize fluorescence microscope apoptosis situation map, hikonin and 5-FU is positive controls; Fig. 6 B is the quantitative analysis figure of 6A figure.
Interpretation of result
Be 1.40 μMs with BSNQ(final concentration) handler's hepatoma Hep G 2 cells 0,3,6,12, after 24h, carry out the two dye experiment of AnnexinV-FITC/PI, and at fluorescence microscope.As can be seen from Fig. 6 B, along with the continuous increase of drug exposure times, AnnexinV-FITC fluorescence intensity also strengthens gradually, and its apoptosis degree also significantly increases.Especially, when the time is 24h, the fluorescence intensity of cell is the highest.BSNQ effectively can induce the apoptosis of HepG2 cell, and in time-dependent manner.
3, with BSNQ process Huh7 cell, BSNQ is detected to the apoptosis of people liver cancer Huh7 cell
Adopt above-mentioned experimental technique, the experimental result obtained is shown in Fig. 7 A and Fig. 7 B, and wherein Fig. 7 A is with after BSNQ process Huh7 cell, and utilize fluorescence microscope apoptosis situation map, shikonin and 5-FU is positive controls; Fig. 7 B is the quantitative analysis figure of Fig. 7 A.
Interpretation of result
Be 1.40 μMs with BSNQ(final concentration) handler liver cancer Huh7 cell 0,3,6,12, after 24h, carry out the two dye experiment of AnnexinV-FITC/PI, and at fluorescence microscopy Microscopic observation.As can be seen from Fig. 7 B, along with the continuous increase of drug exposure times, AnnexinV-FITC fluorescence intensity also strengthens gradually, and its apoptosis degree also significantly increases.Especially, when the time is 24h, the fluorescence intensity of cell is the highest.
In sum, BSNQ(IC
50: 1.40 μMs) apoptosis of Hep3B cells, HepG2 and Huh7 cell can be induced, its cancer cell-apoptosis ability raises gradually along with the increase of time.
Claims (1)
1. 2-fourth sulfoxide-1,4-naphthoquinone compound, is characterized in that the structural formula of this compound is:
.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107793380A (en) * | 2017-10-30 | 2018-03-13 | 黑龙江八农垦大学 | Naphthoquinones of 2,3 2 third sulfone of epoxy, 5,8 dimethoxy 1,4 and preparation method thereof and the medicine containing it |
| CN108299257A (en) * | 2017-10-30 | 2018-07-20 | 黑龙江八农垦大学 | Ten disulfoxide of 2- -1,4-naphthoquinone compound, preparation method and using the compound as the drug of active constituent |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107793380A (en) * | 2017-10-30 | 2018-03-13 | 黑龙江八农垦大学 | Naphthoquinones of 2,3 2 third sulfone of epoxy, 5,8 dimethoxy 1,4 and preparation method thereof and the medicine containing it |
| CN108299257A (en) * | 2017-10-30 | 2018-07-20 | 黑龙江八农垦大学 | Ten disulfoxide of 2- -1,4-naphthoquinone compound, preparation method and using the compound as the drug of active constituent |
| CN107793380B (en) * | 2017-10-30 | 2021-04-23 | 黑龙江八一农垦大学 | 2, 3-epoxy-2-propyl sulfone-5, 8-dimethoxy-1, 4-naphthoquinone, preparation method thereof and medicine containing same |
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