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CN112851535B - Synthesis and application of novel 4,4' - (((polyhalogenated phenyl) azadiyl) bis (methylene)) dibenzoic acid - Google Patents

Synthesis and application of novel 4,4' - (((polyhalogenated phenyl) azadiyl) bis (methylene)) dibenzoic acid Download PDF

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CN112851535B
CN112851535B CN202110093081.4A CN202110093081A CN112851535B CN 112851535 B CN112851535 B CN 112851535B CN 202110093081 A CN202110093081 A CN 202110093081A CN 112851535 B CN112851535 B CN 112851535B
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张淑华
曾玉梅
张少美
李光照
龙威
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Guangdong University of Petrochemical Technology
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Abstract

The present invention discloses novel 4,4' - ((((polyhalophenyl) azepinyl) bis (methylene)) dibenzoic acid (H) 2 L) organic matter and a preparation method thereof, belonging to the field of anti-cancer drugs. The method mainly takes 4-bromomethyl benzoate as a main functional part, selects one of 2,4, 6-trichloroaniline, 3-chloro-4-amino benzotrifluoride, p-trifluoromethylaniline and 2,4, 6-tribromoaniline as an electron-donating unit, and synthesizes a novel organic halogen-containing compound (H) through substitution reaction 2 L). The compound has good anticancer activity and low toxicity to normal cells. The invention has simple preparation process, low cost, good repeatability and high yield, and is a promising anti-cancer medicament.

Description

Synthesis and application of novel 4,4' - ((polyhalogenated phenyl) azadiyl) bis (methylene) dibenzoic acid
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to synthesis of an organic compound 4,4' - (((polyhalogenated phenyl) azadiyl) bis (methylene)) dibenzoic acid and application thereof in the field of anticancer.
Background
Day 2,4 of each year is a worldwide cancer day, and establishment of a worldwide cancer day shows a global consensus to overcome the promise and expectation of cancer. In China, cancer has become the leading cause of death, and morbidity and mortality rates are rising, posing a great threat to public health. Statistically, over 280 million people die of cancer in 2015, with an average of 7500 people per day. The search for effective anti-cancer drugs has been one of the major challenges facing medicinal chemists. Halogen-containing compounds are always paid attention to by medicinal chemists as important anti-cancer drugs, and the research of synthesizing novel organic halogen-containing compounds and finding halogen-containing compounds with good anti-cancer effects is one of the research hotspots of medicinal chemistry.
Disclosure of Invention
1. Object of the invention
The invention aims to provide a compound with anticancer functionNovel active organic halogen-containing compounds (H) 2 L), and particularly relates to synthesis and application of 4,4' - (((polyhalogenated phenyl) azadiyl) bis (methylene)) dibenzoic acid, wherein methyl 4-bromomethylbenzoate is mainly used as a main functional part, 2,4, 6-trichloroaniline, 3-chloro-4-amino trifluorotoluene, p-trifluoromethylaniline and 2,4, 6-tribromoaniline are selected as electron donor units and are respectively synthesized through substitution reaction, and the compound has good anticancer activity.
2. Technical scheme
In order to solve the problems, the technical scheme adopted by the invention is as follows:
the invention provides a novel organic halogen-containing compound with anticancer activity, which is 4,4' - (((polyhalogenated phenyl) azadiyl) bis (methylene)) dibenzoic acid, and the structural general formula of the compound is as follows:
Figure GDA0003749880080000011
wherein R is 3 Selected from CF 3 Or one of halogen atoms;
when R is 3 When it is a halogen atom, R 1 ＝R 2 ＝R 3 ，
When R is 3 Is CF 3 When R is 1 One selected from halogen atom or H, R 2 Is selected from one of halogen or H.
Preferably, the halogen atom comprises one of Br or Cl.
Preferably, when R is 3 Is CF 3 When R is 1 ＝H，R 2 Selected from one of halogen or H.
Preferably, the novel organic halogen-containing compound is specifically:
H 2 L 1 :4,4' - (((2, 4, 6-trichloro) azepinyl) bis (methylene)) dibenzoic acid, C 22 H 16 NO 4 Cl 3 The structural formula is shown as formula 1:
wherein,
Figure GDA0003749880080000021
preferably, the novel organic halogen-containing compound is specifically:
H 2 L 2 :4,4' - (((2-chloro-4-trifluoromethyl) azepinyl) bis (methylene)) dibenzoic acid, C 23 H 17 NO 4 F 3 Cl, structural formula shown in formula 2:
wherein,
Figure GDA0003749880080000022
preferably, the above-mentioned novel organic halogen-containing compounds are specifically:
H 2 L 3 :4,4' - (((4-trifluoromethyl) azepinyl) bis (methylene)) dibenzoic acid, C 23 H 18 NO 4 F 3 The structural formula is shown as formula 3:
wherein,
Figure GDA0003749880080000031
preferably, the novel organic halogen-containing compound is specifically:
H 2 L 4 :4,4' - (((2, 4, 6-tribromo) azepinyl) bis (methylene)) dibenzoic acid, C 22 H 16 NO 4 Br 3 The structural formula is shown as formula 4:
wherein,
Figure GDA0003749880080000032
the invention also provides a preparation method of the novel organic halogen-containing compound, which takes the methyl 4-bromomethylbenzoate as a functional part and polyhalogenated aniline as an electron donor unit to synthesize the compound through substitution reaction.
Preferably, the electron donor unit includes one of 2,4, 6-trichloroaniline, 3-chloro-4-aminotrifluorotoluene, p-trifluoromethylaniline, and 2,4, 6-tribromoaniline.
Preferably, the preparation method comprises the following steps: respectively dissolving 4-bromomethyl benzoate and an electron donor unit in DMF; mixing and heating dropwise under the protection of nitrogen for reaction; washing the reaction mixed solution in the S2 with water, extracting with DCM, removing water, and evaporating until a small amount of product is remained; wrapping the product in the S3 with silica gel powder, and drying; separating the product in the S4 by a column chromatography separation method, wherein developing agents of 2,4, 6-trichloroaniline, 2,4, 6-tribromoaniline and p-trifluoromethylaniline are PE and DCM, developing agents of 3-chloro-4-amino benzotrifluoride are PE and EA, and four product points appear on a thin-layer plate from low to high; and (3) selecting a third point from low to high, dissolving in ethanol, adding a NaOH solution, carrying out condensation reflux in a water bath, adjusting the pH value to 2.5-3.5, separating out a white precipitate, washing with water, filtering, and drying a filter cake to obtain a target product.
The invention also provides the novel organic halogen-containing compound H 2 L 1 The synthesis method comprises the following steps:
(1) Weighing 2,4, 6-trichloroaniline and analytically pure potassium carbonate, and dissolving in N, N-Dimethylformamide (DMF);
preferably, the amount of potassium carbonate is 5 to 10mmol and the amount of DMF is 10 to 30mL relative to 5mmol of 2,4, 6-trichloroaniline.
(2) Weighing methyl 4-bromomethylbenzoate, dissolving in analytically pure DMF solution, and transferring to a constant pressure funnel;
preferably, the amount of methyl 4-bromomethylbenzoate is 20 to 40mmol and the amount of DMF is 10 to 30mL relative to 5mmol of 2,4, 6-trichloroaniline.
(3) And (3) under the water bath condition, controlling the dropping speed of the constant-pressure funnel, dropping the solution obtained in the step (2) into the solution prepared in the step (1) at a constant speed, and strictly reacting in a nitrogen atmosphere in the whole reaction process.
Preferably, the water bath temperature is 70-90 ℃, and the reaction time is 8-16h.
(4) And (4) washing the mixed solution after the reaction in the step (3), extracting with Dichloromethane (DCM) to remove water, and then spinning off the solvent by using a rotary evaporator until 10-20mL of the product is remained.
Preferably, the washing is performed a plurality of times, and further, the washing is performed four times, which can also be adjusted according to the actual situation.
Preferably, the DCM extraction is performed several times, further three times, which can also be adjusted to the actual situation.
Preferably, the water removal can be performed by first removing water with saturated saline solution and then performing water absorption with anhydrous sodium sulfate.
(5) And (5) wrapping the product obtained in the step (4) with silica gel powder, and drying for dry-method sample loading.
Preferably, the drying temperature is 50-60 ℃, and the drying time is 12-24h.
(6) The separation of the target product was performed using column chromatography with Petroleum Ether (PE) and DCM as developing agents and DCM and excess reactant was recovered by rotary evaporation. Four points can be observed on the thin-layer plate, the first point and the third point from low to high are required product points, the first point is a single-substituted product point, and the third point is a double-substituted product point (target product).
Preferably, PE: DCM = (4-6): 1 (V) 1 :V 2 ). Further, PE: DCM =5 (V 1 :V 2 )。
(7) And (3) dissolving the product obtained in the step (6) in analytically pure ethanol, slowly adding NaOH, carrying out condensation reflux in a water bath, adjusting the pH value of the solution to 2.5-3.5, separating out a white precipitate, washing the white precipitate with water, filtering, and drying a filter cake to obtain the target product.
Preferably, the amount of ethanol is 40-50mL and the amount of NaOH is 26.4-52.8mL.
Preferably, the temperature of the water bath for condensing reflux is 70-90 ℃, and the condensing time is 2-4h.
Preferably, the pH of the adjusting solution is adjusted by using 0.5mol/L HCl.
Preferably, the filter cake drying temperature is 50-60 ℃.
The invention also provides the novel organic halogen-containing compound H 2 L 2 The synthesis process of (a) basically corresponds to the above H 2 L 1 The synthesis method is the same, and the difference is that: weighing 3-chloro-4-amino benzotrifluoride in the step (1), wherein the developing agents used in the step (6) are Petroleum Ether (PE) and Ethyl Acetate (EA).
Preference is given toIn addition, PE: EA = (14-16): 1 (V) 1 :V 2 ). Further, PE: EA =15 (V 1 :V 2 )。
The invention also provides the novel organic halogen-containing compound H 2 L 3 The synthesis process of (a) basically corresponds to the above H 2 L 1 The synthesis method is the same, and the difference is that: weighing p-trifluoromethylaniline in the step (1).
The invention also provides the novel organic halogen-containing compound H 2 L 4 The synthesis process of (a) basically corresponds to the above H 2 L 1 The synthesis method is the same, and the difference is that: weighing 2,4, 6-tribromoaniline in the step (1).
The novel organic halogen-containing compound and the pharmaceutically acceptable salt thereof are applied to the preparation of anticancer drugs.
The preparation method of the novel organic halogen-containing compound is applied to the preparation of anticancer drugs.
3. Advantageous effects
Compared with the prior art, the invention has the beneficial effects that:
(1) The novel organic halogen-containing compound has excellent anticancer activity, as shown in tables 1 and 2, wherein the novel organic halogen-containing compound has stronger apoptosis induction capability on BEL-7404 human hepatoma cell strains and Hela cervical carcinoma cells, and especially has H (human embryonic stem cell) activity 2 L 2 The anticancer activity of the compound is higher than that of the currently commonly used 5-fluorouracil, H 2 L 1 Also close to 5-fluorouracil.
(2) The novel organic halogen-containing compounds of the present invention have anticancer activity and low toxicity to normal cells, as shown in tables 1 and 2, wherein H is 2 L 1 、H 2 L 2 The toxicity is about 1/3 of commonly used 5-fluorouracil, H 2 L 3 、H 2 L 4 The toxicity is about 1/2 of commonly used 5-fluorouracil.
(3) The preparation method of the novel organic halogen-containing compound has the advantages of simple process, low cost, good repeatability and high yield.
Drawings
FIG. 1 isOrganic matter H 2 L 1 -H 2 L 4 A schematic structural diagram;
FIG. 2 is H 2 L 1 -H 2 L 4 A synthesis reaction equation;
FIG. 3 shows an organic substance H 2 L 1 (ii) spectrum H;
FIG. 4 shows an organic substance H 2 L 1 Spectrum C of (1);
FIG. 5 organic H 2 L 2 (ii) spectrum H;
FIG. 6 organic H 2 L 3 Spectrum H of (1);
FIG. 7 organic H 2 L 4 Spectrum H of (1);
FIG. 8 organic H 2 L 4 Spectrum C of (2).
Detailed Description
The invention is further described with reference to specific examples.
It should be noted that the terms "upper", "lower", "left", "right" and "middle" used in the present specification are for the sake of clarity, and are not intended to limit the scope of the present invention, and changes or adjustments of the relative relationship thereof may be made without substantial technical changes.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs; as used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
As used herein, the term "about" is used to provide the flexibility and inaccuracy associated with a given term, measure or value. The degree of flexibility for a particular variable can be readily determined by one skilled in the art.
As used herein, at least one of the terms "is intended to be synonymous with one or more of. For example, "at least one of a, B, and C" explicitly includes a only, B only, C only, and combinations thereof, respectively.
Concentrations, amounts, and other numerical data may be presented herein in a range format. It is to be understood that such a range format is used merely for convenience and brevity and should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. For example, a numerical range of about 1 to about 4.5 should be interpreted to include not only the explicitly recited limit values of 1 to about 4.5, but also include individual numbers (such as 2, 3, 4) and sub-ranges (such as 1 to 3, 2 to 4, etc.). The same principle applies to ranges reciting only one numerical value, such as "less than about 4.5," which should be construed as including all such values and ranges. Further, such interpretation should apply regardless of the breadth of the range or the characteristics being described.
Any steps recited in any method or process claims may be executed in any order and are not limited to the order presented in the claims.
Example 1
This example provides novel organic halogen-containing compounds having anticancer activity, 4' - (((2, 4, 6-trichloro) azepinyl) bis (methylene)) dibenzoic acid (H) 2 L 1 ) The molecular formula is: c 22 H 16 NO 4 Cl 3 (ii) a The molecular weight is: 464.73g/mol.
This example provides H 2 L 1 The preparation method comprises the following steps:
(1) Weighing 10mL of analytically pure DMF in a 100mL single-neck flask, weighing analytically pure 2,4, 6-trichloroaniline (5 mmol, 0.9823g) and analytically pure potassium carbonate (5 mmol, 0.69105g), and dissolving in the 100mL single-neck flask filled with 10mL of analytically pure DMF;
(2) Analytically pure methyl 4-bromomethylbenzoate (20mmol, 4.5814g) was weighed out and dissolved in a 100mL beaker containing 10mL of analytically pure DMF solution, which was transferred to a constant pressure funnel.
(3) Under the condition of 70 ℃ water bath, the dropping speed of a constant-pressure funnel is controlled, the constant speed is dripped into a prepared single-neck flask, and the whole reaction process strictly reacts for 8 hours in a nitrogen atmosphere.
(4) The mixture obtained after 8 hours of reaction was washed with water four times, then extracted with analytically pure DCM three times, then dewatered with saturated brine, and then water absorbed with anhydrous sodium sulfate, and the solvent was spun off with a rotary evaporator, leaving about 10-20mL of product.
(5) And (4) wrapping the product in the step (4) with silica gel powder, and putting the product in an oven at 50-60 ℃ overnight for dry-method sample loading.
(6) The isolation of the desired product was performed using column chromatography separation with PE and DCM as developing agents, PE: DCM =5 (V 1 :V 2 ) DCM and excess reaction were recovered by rotary evaporation. Four points can be observed on the thin-layer plate, the first point and the third point from low to high are required product points, the first point is a single-substituted product point, and the third point is a double-substituted product point (target product).
(7) Dissolving the product of the step (6) in 40-50mL of analytically pure ethanol, slowly adding 26.4mL of 10% NaOH (3 eq) and carrying out condensation reflux for 2h under 70 ℃ water bath, adjusting the pH of the solution to 2.5-3.5 by using 0.5mol/L HCl, then precipitating white precipitate, washing and filtering the white precipitate, and drying the filter cake at 50 ℃ to obtain 0.1089g of the product with the yield of 23.43%.
The product was identified and its H spectrum is shown in figure 3, 1 H NMR((CD) 3 SO,500 MHz) δ (TMS, ppm): 12.89-12.85 (s, 2H), 7.88-7.85 (d, 4H), 7.57-7.55 (s, 2H), 7.46-7.42 (d, 4H), 4.33-4.30 (s, 4H) MS: m/z =464.73; the spectrum of C is shown in figure 4, 13 C，((CD) 3 SO,500 MHz) δ (TMS, ppm): 167.63-167.58 (s, 2C), 143.28-142.82 (d, 3C), 136.72-136.62 (s, 1C), 130.98-130.89 (s, 1C), 130.33-130.24 (s, 1C), 129.84-129.65 (s, 5C), 129.59-129.35 (d, 7C), 56.04-55.84 (s, 2C), indicating that the product obtained is the target product, i.e.: 4,4' - (((2, 4, 6-trichloro) azepinyl) bis (methylene)) dibenzoic acid (H) 2 L 1 )。
Example 2
This example provides a novel organic halogen-containing compound having anti-cancer activity, which is 4,4' - (((2, 4, 6-trichloro) azepinyl) bis (methylene)) dibenzoic acid (H) 2 L 1 ) The molecular formula is: c 22 H 16 NO 4 Cl 3 (ii) a The molecular weight is: 464.73g/mol.
This example provides H 2 L 1 The preparation method comprises the following steps:
(1) 30mL of analytically pure DMF was weighed into a 100mL single-neck flask, and analytically pure 2,4, 6-trichloroaniline (5mmol, 0.9823g) and analytically pure potassium carbonate (10mmol, 1.3821g) were weighed and dissolved in a 100mL single-neck flask containing 30mL of analytically pure DMF;
(2) Analytically pure methyl 4-bromomethylbenzoate (40mmol, 9.1628g) was weighed out and dissolved in a 100mL beaker with 30mL of analytically pure DMF solution and transferred to a constant pressure funnel.
(3) And (3) under the condition of water bath at 90 ℃, controlling the dropping speed of the constant-pressure funnel, dropwise adding the constant-speed funnel into a prepared single-neck flask at a constant speed, and strictly reacting for 16 hours in a nitrogen atmosphere in the whole reaction process.
(4) The mixture obtained after 16 hours of reaction was washed with water four times, then extracted with analytically pure DCM three times, then dewatered with saturated brine, and then water was absorbed with anhydrous sodium sulfate, and the solvent was spun off with a rotary evaporator, and the remaining product was about 10-20 mL.
(5) And (4) wrapping the product in the step (4) with silica gel powder, and putting the product in an oven at 50-60 ℃ overnight for dry-method sample loading.
(6) The isolation of the target product was performed using column chromatography separation with PE and DCM as developing agents, PE: DCM =4 (V 1 :V 2 ) DCM and excess reaction were recovered by rotary evaporation. Four points can be observed on the thin-layer plate, the first point and the third point from low to high are required product points, the first point is a single-substituted product point, and the third point is a double-substituted product point (target product).
(7) Dissolving the product obtained in the step (6) in 40-50mL of analytically pure ethanol, slowly adding 52.8mL of 10% NaOH (3 eq), carrying out 4h condensation reflux in a water bath at 90 ℃, adjusting the pH of the solution to 2.5-3.5 by using 0.5mol/L HCl, then precipitating white precipitate, washing and filtering the white precipitate, and drying a filter cake at 60 ℃ to obtain the product.
The identification of the product indicates that the product obtained is the target product, namely: 4,4' - (((2, 4, 6-trichloro) azepinyl) bis (methylene)) dibenzoic acid (H) 2 L 1 )。
Example 3
This example provides a novel organic halogen-containing compound having anti-cancer activity which is 4,4' - (((2-chloro-4-trifluoromethyl) azepinyl) bis (methylene)) dibenzoic acid (H) 2 L 2 ) The molecular formula is: c 23 H 17 NO 4 F 3 Cl; the molecular weight is: 463.84g/mol.
This example provides H 2 L 2 The preparation method of (1) is basically the same as that of the preparation method of H in example 1 2 L 1 The synthesis method is the same, and the difference is that: weighing 3-chloro-4-aminobenzotrifluoride in the step (1), wherein the developing agents used in the step (6) are Petroleum Ether (PE) and Ethyl Acetate (EA), and PE: EA =15 1 :V 2 ) To obtain 0.8928g of product with 37.99% yield.
The product was identified and its H spectrum is shown in FIG. 5, 1 H NMR(CDCl 3 400 MHz) δ (TMS, ppm): 4.69-4.74 (d, 4H), 7.32-7.33 (s, 1H), 7.41-7.42 (s, 1H), 7.44-7.48 (d, 3H), 7.62-7.64 (s, 2H), 7.94-7.98 (d, 4H), 11.41-11.43 (s, 2H). MS: m/z =463.84, indicating that the product obtained is the target product, namely: 4,4' - (((2-chloro-4-trifluoromethyl) azepinyl) bis (methylene)) dibenzoic acid (H) 2 L 2 )。
Example 4
This example provides a novel organic halogen-containing compound having anti-cancer activity which is 4,4' - (((4-trifluoromethyl) azepinyl) bis (methylene)) dibenzoic acid (H) 2 L 3 ) The molecular formula is: c 23 H 18 NO 4 F 3 (ii) a The molecular weight is: 429.40g/mol.
This example provides H 2 L 3 The procedure of (1) is essentially the same as in example 1H 2 L 1 The synthesis method is the same, and the difference is that: weighing p-trifluoromethylaniline in the step (1), wherein in the step (6), the weight ratio of PE: DCM =6 1 :V 2 ) 0.4206g of product is obtained with a yield of 19.59%.
The product was identified and its H spectrum is shown in figure 6, 1 H NMR(CDCl 3 400 MHz) δ (TMS, ppm): 4.53-4.58 (s, 4H), 6.51-6.55 (d, 2H), 7.32-7.37 (d, 2H), 7.43-7.47 (d, 4H), 7.68-7.72 (s, 2H), 8.09-8.14 (d, 4H) MS: m/z =429.40, indicating that the product obtained is the target product, namely: 4,4' - (((4-trifluoromethyl) azepinyl) bis (methylene)) dibenzoic acid (H) 2 L 3 )。
Example 5
This example provides novel organic halogen-containing compounds having anticancer activity, 4' - (((2, 4, 6-tribromo) azepinyl) bis (methylene)) dibenzoic acid (H) 2 L 4 ) The molecular formula is: c 22 H 16 NO 4 Br 3 (ii) a The molecular weight is: 589.09g/mol.
This example provides H 2 L 4 The procedure of (1) is essentially the same as that of example 1H 2 L 1 The synthesis method is the same, and the difference is that: in step (1), 2,4, 6-tribromoaniline was weighed out to give 0.5466g of product, yield 24.63%.
The product was identified and its H spectrum is shown in figure 7, 1 H NMR(CDCl 3 400 MHz) δ (TMS, ppm): 4.48-4.51 (s, 4H), 7.48-7.50 (s, 1H), 7.50-7.53 (d, 4H), 7.61-7.64 (d, 4H), 8.06-8.07 (s, 1H), 8.08-8.10 (s, 1H), 11.08-11.09 (s, 2H) MS: m/z =589.09; the spectrum of C is shown in figure 8, 13 C，(CDCl 3 400 MHz) delta (TMS, ppm) 51.55-51.53 (s, 2C), 108.8-108.8 (s, 1C), 117.74-117.57 (s, 2C), 128.12-128.17 (s, 4C), 130.50-130.59 (s, 4C), 133.84-133.85 (s, 1C), 135.02-135.08 (s, 4C), 144.98-145.02 (s, 2C), 170.42-170.52 (s, 2C), indicating that the product obtained is the target product, namely: 4,4' - (((2, 4, 6-tribromo) azepinyl) bis (methylene)) dibenzoic acid (H) 2 L 4 )。
Example 6
This example uses 5-fluorouracil (5-FU) as a referenceH is determined by MTT method 2 L 1 -H 2 L 4 Growth inhibition rate and IC of organic matter on BEL-7404 human liver cancer cell line, hela cervical carcinoma cell and HL-7702 normal liver cell line 50 The value is obtained.
The selected cell line is 5% CO 2 Culturing in 37 deg.C culture box, wherein the culture solution is DMEM or RPMI-1640 culture solution containing 10% newborn bovine serum and streptomycin 100U/mL each. The growth of the cells was observed using an inverted microscope, and cells were subjected to digestion passage with 0.25% trypsin at the time of inoculation and selected for cytotoxicity test in the logarithmic growth phase.
Inoculating the test tumor cells in a culture medium containing 10% newborn calf serum RPMI1640, at 37 ℃ 5% CO 2 Culturing in an incubator under saturated humidity condition, changing culture medium 2-3 times per week, and subculturing once in 6-7 days. Cancer cells in the culture solution were added at a concentration of 2X 10 4 Each/mL was inoculated in a 96-well cell culture plate at 190. Mu.L per well volume and cultured at 37 ℃ for one day in 5% CO2. After the cells adhere to the wall, 10 mu L of test compound with different concentrations is added into each hole, wherein the concentration of dimethyl sulfoxide (DMSO) is less than or equal to 1 percent, and meanwhile, a corresponding negative control group is set as that no drug exists in the culture solution, and only the test cells and the same amount of DMSO exist. For in-well testing, six replicates per sample were used. After two days of incubation, MTT reagent (5 mg/mL, 10. Mu.L) was added to each well and incubation continued for 4h, after completion of the incubation, the supernatant was aspirated. Then, 150. Mu.L of DMSO was added to each well, and the OD value of each well at a wavelength of 490nm was measured by a microplate reader, and the cell proliferation inhibition rate was calculated by the formula of inhibition rate (%) = ((OD value of control group-OD value of sample group)/OD value of control group). Times.100%. Separately calculating each IC by Bliss method 50 The value is obtained. All experiments were repeated 3 times and averaged.
After 48H of treatment with a drug concentration of 20. Mu.M, compound H 2 L 1 -H 2 L 4 And 5-FU at 20. Mu.M in human body are shown in Table 1, and Compound H 2 L 1 -H 2 L 4 All show inhibition on cancer cells, wherein H 2 L 2 To BEL-7404 andhela has the inhibition rates of 65.03 +/-0.46 and 70.63 +/-1.07 which are higher than the inhibition rate of a reference substance 5-FU, and H 2 L 1 The inhibition rate of the compound on HeLa is close to that of 5-fluorouracil. Furthermore, compounds H 2 L 1 -H 2 L 4 All show lower toxicity to normal HL-7702 cells than to the reference 5-FU, wherein H 2 L 1 、H 2 L 2 The toxicity is about 1/3 of commonly used 5-fluorouracil, H 2 L 3 、H 2 L 4 The toxicity is about 1/2 of commonly used 5-fluorouracil.
Compound H 2 L 1 -H 2 L 4 And IC of 5-FU on various types of cells of the human body 50 The value (. Mu.M) is shown in Table 2, IC 50 The measured experiment result is consistent with the inhibition rate, H 2 L 2 IC of BEL-7404 and Hela in pair 50 The values are respectively 9.06 +/-1.15 mu M and 5.01 +/-0.48 mu M, which are all lower than the IC corresponding to 5-fluorouracil 50 The value is obtained.
The above experimental results show that H 2 L 2 Has stronger apoptosis induction capability on BEL-7404 human hepatoma cell strains and Hela cervical carcinoma cells, has lower toxicity on normal cells, and is a promising anticancer drug.
TABLE 1 Compound H 2 L 1 -H 2 L 4 And the inhibition rate of 5-fluorouracil to various types of cells of human body under the condition of 20 mu M
Figure GDA0003749880080000101
TABLE 2 Compound H 2 L 1 -H 2 L 4 And IC of 5-fluorouracil on various types of cells of the human body 50 Value (μ M)
Figure GDA0003749880080000102

Claims (8)

1. A novel organic halogen-containing compound is characterized in that the compound has the following structural general formula:
Figure FDA0003796929560000011
wherein R is 3 Selected from CF 3 Or a kind of a halogen atom, or a halogen atom,
when R is 3 When it is a halogen atom, R 1 ＝R 2 ＝R 3 ，
When R is 3 Is CF 3 When R is 1 One selected from halogen atom or H, R 2 Selected from one of halogen atoms or H.
2. A novel organic halogen-containing compound according to claim 1, characterized in that said halogen atom is selected from one of Br or Cl.
3. A novel organic halogen-containing compound according to claim 2, characterized in that said compound is:
R 1 ＝R 2 ＝R 3 ＝Cl；
or R 3 ＝CF 3 ，R 1 ＝H，R 2 ＝Cl；
Or R 3 ＝CF 3 ，R 1 ＝R 2 ＝H；
Or R 1 ＝R 2 ＝R 3 ＝Br。
4. A method for producing a novel organic halogen-containing compound, characterized in that the novel organic halogen-containing compound is the novel organic halogen-containing compound according to claim 3, synthesized by substitution reaction using methyl 4-bromomethylbenzoate as a functional moiety and one of 2,4, 6-trichloroaniline, 3-chloro-4-aminotrifluoromethylaniline, p-trifluoromethylaniline, and 2,4, 6-tribromoaniline as an electron donating unit.
5. A method according to claim 4, characterized in that said method comprises:
s1: respectively dissolving 4-bromomethyl benzoate and an electron donor unit in DMF;
s2: mixing and heating dropwise under the protection of nitrogen for reaction;
s3: washing the reaction mixed solution in the S2 with water, extracting with DCM, removing water, and evaporating until a small amount of product is remained;
s4: wrapping the product in the S3 with silica gel powder, and drying;
s5: separating the product in the S4 by a column chromatography separation method, wherein developing agents of 2,4, 6-trichloroaniline, 2,4, 6-tribromoaniline and p-trifluoromethylaniline are PE and DCM, developing agents of 3-chloro-4-amino benzotrifluoride are PE and EA, and four product points appear on a thin-layer plate from low to high;
s6: and (3) selecting the third point from low to high in S5, dissolving in ethanol, adding a NaOH solution, carrying out condensation reflux in a water bath, adjusting the pH value to 2.5-3.5, separating out a white precipitate, washing with water, filtering, and drying a filter cake to obtain a target product.
6. The method of claim 5, wherein the method comprises:
the reaction in S1 is carried out under the condition of potassium carbonate, relative to 5mmol of electron donor units, the amount of potassium carbonate is 5-10mmol, the amount of DMF for dissolving the electron donor units is 10-30mL, the amount of methyl 4-bromomethylbenzoate is 20-40mmol, and the amount of DMF for dissolving the methyl 4-bromomethylbenzoate is 10-30mL; and/or 4-bromomethyl benzoate is transferred to a constant pressure funnel after being dissolved in DMF;
in S2, heating is carried out through a water bath, the temperature is 70-90 ℃, and the reaction time is 8-16h; and/or when the mixture is dropwise mixed, controlling the dropping speed of the constant-pressure funnel, and dropwise adding the DMF solution in which the methyl 4-bromomethylbenzoate is dissolved into the solution in which the electron-donating unit is dissolved at a constant speed;
s4, drying at the temperature of 50-60 ℃ for 12-24h;
in S5, the volume ratio of PE to DCM = 5;
in S6, the dosage of ethanol is 40-50mL relative to 5mmol of electron donor units; the temperature of the water bath for condensing and refluxing is 70-90 ℃, and the condensing time is 2-4h; the drying temperature of the filter cake is 50-60 ℃.
7. Use of a novel organic halogen-containing compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3 in the manufacture of a medicament for the treatment of cancer selected from liver cancer or cervical cancer.
8. Use of the novel organic halogen-containing compound of any one of claims 4 to 6 for the preparation of an anticancer drug, said cancer being selected from liver cancer or cervical cancer.
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