CN112851535A - 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 PDFInfo
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Abstract
The present invention discloses novel 4, 4' - (((polyhalophenyl) azepinyl) bis (methylene)) dibenzoic acid (H)2L) organic matter and a preparation method thereof, belonging to the field of anti-cancer drugs. The method mainly takes 4-bromomethylbenzoic acid methyl ester as a main functional part, selects one of 2,4, 6-trichloroaniline, 3-chloro-4-amino trifluorotoluene, p-trifluoromethylaniline and 2,4, 6-tribromoaniline as an electron-donating unit, and synthesizes a novel organic halogen-containing compound (H) through substitution reaction2L). 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,is a promising anti-cancer drug.
Description
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. Cancer has become the leading cause of death in china, and morbidity and mortality are rising, posing a significant threat to public health. Statistically, over 280 million people died from cancer in 2015, averaging 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. Objects of the invention
The invention aims to provide a novel organic halogen-containing compound (H) with anticancer activity2L), 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 donating 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:
wherein R is3Selected from CF3Or one of halogen atoms;
when R is3When it is a halogen atom, R1＝R2＝R3，
When R is3Is CF3When R is1One selected from halogen atom or H, R2Is selected from one of halogen or H.
Preferably, the halogen atom comprises one of Br or Cl.
Preferably, when R is3Is CF3When R is1＝H，R2Is selected from one of halogen or H.
Preferably, the novel organic halogen-containing compound is specifically:
H2L1: 4, 4' - (((2, 4, 6-trichloro) azepinyl) bis (methylene)) dibenzoic acid, C22H16NO4Cl3The structural formula is shown as formula 1:
wherein R is1＝R2＝R3＝Cl
Formula 1
Preferably, the novel organic halogen-containing compound is specifically:
H2L2: 4, 4' - (((2-chloro-4-trifluoromethyl) azepinyl) bis (methylene)) dibenzoic acid, C23H23NO4F3Cl, structural formula shown in formula 2:
wherein R is1＝H，R2＝Cl，R3＝CF3
Formula 2
Preferably, the novel organic halogen-containing compound is specifically:
H2L3: 4, 4' - (((4-trifluoromethyl) azepinyl) bis (methylene)) dibenzoic acid, C23H18NO4F3The structural formula is shown as formula 3:
wherein R is1＝R2＝H，R3＝CF3
Formula 3
Preferably, the novel organic halogen-containing compound is specifically:
H2L4: 4, 4' - (((2, 4, 6-tribromo) azepinyl) bis (methylene)) dibenzoic acid, C22H20NO4Br3The structural formula is shown as formula 4:
wherein R is1＝R2＝R3＝Br
Formula 4
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 comprises one of 2,4, 6-trichloroaniline, 3-chloro-4-aminotrifluorobenzene, 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 H2L1The 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 5-10mmol and the amount of DMF is 10-30mL 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 20-40mmol and the amount of DMF is 10-30mL 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 temperature of the water bath is 70-90 ℃, and the reaction time is 8-16 h.
(4) And (4) washing the mixed solution after the reaction in the step (3) with water, extracting with Dichloromethane (DCM), removing water, and then using a rotary evaporator to spin out the solvent 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 (4) 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 12-24 h.
(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:V2). Further, PE: DCM ═ 5:1 (V)1:V2)。
(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 26.4-52.8 mL.
Preferably, the temperature of the water bath for condensing reflux is 70-90 ℃, and the condensing time is 2-4 h.
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 H2L2The synthesis process of (a) basically corresponds to the above H2L1The 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).
Preferably, PE: EA ═ 14-16: 1 (V)1:V2). Further, PE: EA is 15:1 (V)1:V2)。
The invention also provides the novel organic halogen-containing compound H2L3The synthesis process of (a) basically corresponds to the above H2L1The 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 H2L4The synthesis process of (a) basically corresponds to the above H2L1The 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) activity2L2The anticancer activity of the compound is higher than that of the currently commonly used 5-fluorouracil, H2L1Also 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 is2L1、H2L2The toxicity is about 5-fluorouracil 1/3 commonly used, H2L3、H2L4The toxicity is about 5-fluorouracil 1/2 commonly used.
(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 shows an organic substance H2L1-H2L4A schematic structural diagram;
FIG. 2 is H2L1-H2L4A synthesis reaction equation;
FIG. 3 shows an organic substance H2L1Spectrum H of (1);
FIG. 4 shows an organic substance H2L1Spectrum C of (1);
FIG. 5 organic H2L2Spectrum H of (1);
FIG. 6 organic H2L3Spectrum H of (1);
FIG. 7 organic H2L4Spectrum H of (1);
FIG. 8 organic H2L4Spectrum 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 to include all of the aforementioned values and ranges. Moreover, such an interpretation should apply regardless of the breadth of the range or feature 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)2L1) The molecular formula is: c22H16NO4Cl3(ii) a The molecular weight is: 464.73 g/mol.
This example provides H2L1The preparation method comprises the following steps:
(1) 10mL of analytically pure DMF is weighed into a 100mL single-neck flask, and analytically pure 2,4, 6-trichloroaniline (5mmol,0.9823g) and analytically pure potassium carbonate (5mmol,0.69105g) are weighed and dissolved into 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 with 10mL of analytically pure DMF solution and transferred to a constant pressure funnel.
(3) And (3) under the condition of 70 ℃ water bath, 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 8 hours in a nitrogen atmosphere in the whole reaction process.
(4) The mixture obtained after 8 hours of reaction was washed with water four times, extracted with analytically pure DCM three times, then dewatered with saturated brine, then 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 separation of the target product was performed using column chromatography with PE and DCM as developing agents, PE: DCM ═ 5:1 (V)1:V2) 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 (3eq) and carrying out condensation reflux for 2h under a water bath at 70 ℃, 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 solution, and drying a filter cake at 50 ℃ to obtain 0.1089g of product with the yield of 23.43%.
The product was identified and its H spectrum is shown in figure 3,1H NMR((CD)3SO,500MHz) 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 C is shown in figure 4 of the drawings,13C，((CD)3SO,500MHz) 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, namely: 4, 4' - (((2, 4, 6-trichloro) azepinyl) bis (methylene)) dibenzoic acid (H)2L1)。
Example 2
This example provides novel organic halogen-containing compounds having anticancer activity, 4' - (((2, 4, 6-trichloro) azepinyl) bis (methylene)) dibenzoic acid (H)2L1) The molecular formula is: c22H16NO4Cl3(ii) a The molecular weight is: 464.73 g/mol.
This example provides H2L1The preparation method comprises the following steps:
(1) 30mL of analytically pure DMF is 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) are weighed and dissolved into the 100mL single-neck flask filled with 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, extracted three times with analytically pure DCM, then dewatered with saturated brine, then 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 separation of the target product was performed using column chromatography with PE and DCM as developing agents, PE: DCM ═ 4:1 (V)1:V2) 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 (3eq), 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)2L1)。
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)2L2) The molecular formula is: c23H23NO4F3Cl; the molecular weight is: 469.88 g/mol.
This example provides H2L2The procedure of (1) is essentially the same as that of example 1H2L1The synthesis method is the same, and the difference is that: weighing 3-chloro-4-amino benzotrifluoride in the step (1), wherein the developing agent used in the step (6) is Petroleum Ether (PE) and Ethyl Acetate (EA), and PE: EA is 15:1 (V)1:V2) 0.8928g of product was obtained with a yield of 37.99%.
The product was identified and its H spectrum is shown in figure 5,1H NMR(CDCl3400MHz) 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 469.88, indicating that the product obtained is the target product, namely: 4, 4' - (((2-chloro-4-trifluoromethyl) azepinyl) bis (methylene)) dibenzoic acid (H)2L2)。
Example 4
This example provides novel organic halogen-containing compounds having anticancer activity which are 4, 4' - (((4-trifluoromethyl) azepinyl) bis (methylene)) dibenzoic acid (H)2L3) The molecular formula is: c23H18NO4F3(ii) a The molecular weight is: 429.40 g/mol.
This example provides H2L3The procedure of (1) is essentially the same as that of example 1H2L1The synthesis method is the same, and the difference is that: weighing p-trifluoromethylaniline in the step (1), wherein in the step (6), the PE (DCM) is 6:1 (V)1:V2) 0.4206g of product was obtained in 19.59% yield.
The product was identified and its H spectrum is shown in figure 6,1H NMR(CDCl3,400MHz)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),11.65-11.66(s,1H),11.69-11.71(s,1H) MS: m/z 429.40, indicating that the product obtained is the target product, i.e.: 4, 4' - (((4-trifluoromethyl) azepinyl) bis (methylene)) dibenzoic acid (H)2L3)。
Example 5
This example provides novel organic halogen-containing compounds having anticancer activity, 4' - (((2, 4, 6-tribromo) azepinyl) bis (methylene)) dibenzoic acid (H)2L4) The molecular formula is: c22H20NO4Br3(ii) a The molecular weight is: 465.96 g/mol.
This example provides H2L4The procedure of (1) is essentially the same as that of example 1H2L1The synthesis method is the same, and the difference is that: in the step (1), 2,4, 6-tribromoaniline is weighed to obtain 0.5466g of product, and the yield is 24.63%.
The product was identified and its H spectrum is shown in figure 7,1H NMR(CDCl3400MHz) 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 465.96; the spectrum of C is shown in figure 8,13C，(CDCl3400MHz) 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)2L4)。
Example 6
In this example, H was measured by MTT method using 5-fluorouracil (5-FU) as a reference substance2L1-H2L4Growth 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 line50The value is obtained.
Selected cell lines were in 5% CO2Culturing in 37 deg.C incubator with 10% newborn bovine serum and green chain100U/mL of each of the mycins in DMEM or RPMI-1640 medium. 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.
Test tumor cells were inoculated in culture medium containing 10% newborn calf serum RPMI1640 at 37 ℃ with 5% CO2Culturing 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 104Each/mL was seeded in a 96-well cell culture plate in a volume of 190. mu.L per well and cultured at 37 ℃ under 5% CO2 for one day. 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 (5mg/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 then 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 as: (%). inhibition rate ((OD value of control group-OD value of sample group)/OD value of control group). times.100%. Separately computing each IC by Bliss method50The value is obtained. All experiments were repeated 3 times and averaged.
After 48H of treatment with a drug concentration of 20. mu.M, Compound H2L1-H2L4And 5-FU at 20. mu.M in human body are shown in Table 1, and Compound H2L1-H2L4All show inhibition on cancer cells, wherein H2L2The inhibition rates of BEL-7404 and Hela are 65.03 +/-0.46 and 70.63 +/-1.07 which are higher than the inhibition rate of a reference substance 5-FU, and H is2L1The inhibition rate of the compound on HeLa is close to that of 5-fluorouracil. Furthermore, Compound H2L1-H2L4All show lower toxicity to normal HL-7702 cells than to the reference 5-FU, wherein H2L1、H2L2The toxicity is about 5-fluorouracil 1/3 commonly used, H2L3、H2L4The toxicity is about 5-fluorouracil 1/2 commonly used.
Compound H2L1-H2L4And IC of 5-FU on various types of cells of the human body50The value (. mu.M) is shown in Table 2, IC50The measured experiment result is consistent with the inhibition rate, H2L2IC of BEL-7404 and Hela in pair50The 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-fluorouracil50The value is obtained.
The above experimental results show that H2L2Has 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 H2L1-H2L4And the inhibition rate of 5-fluorouracil to various types of cells of human body under the condition of 20 mu M
TABLE 2 Compound H2L1-H2L4And IC of 5-fluorouracil on various types of cells of the human body50Value (μ M)
Claims (10)
1. A novel organic halogen-containing compound is characterized in that the compound has the following structural general formula:
wherein R is3Selected from CF3Or a halogen atom,
when R is3When it is a halogen atom, R1＝R2＝R3，
When R is3Is CF3When R is1One selected from halogen atom or H, R2Selected from one of halogen atoms or H.
2. A novel organic halogen-containing compound according to claim 1, characterized in that the halogen atom comprises one of Br or Cl.
3. A novel organic halogen-containing compound according to claim 2, characterized in that said compound is:
R1＝R2＝R3cl, name: 4, 4' - (((2, 4, 6-trichloro) azepinyl) bis (methylene)) dibenzoic acid;
or R3＝CF3，R1＝H，R2Cl, name: 4, 4' - (((2-chloro-4-trifluoromethyl) azepinyl) bis (methylene)) dibenzoic acid;
or R3＝CF3，R1＝R2H, name: 4, 4' - (((4-trifluoromethyl) azepinyl) bis (methylene)) dibenzoic acid;
or R1＝R2＝R3Br, name: 4, 4' - (((2, 4, 6-tribromo) azepinyl) bis (methylene)) dibenzoic acid.
4. The preparation method of the novel organic halogen-containing compound is characterized in that the novel organic halogen-containing compound is synthesized by using methyl 4-bromomethylbenzoate as a functional part and polyhalogenated aniline as an electron donor unit through substitution reaction.
5. The method according to claim 4, wherein said electron donor unit comprises one of 2,4, 6-trichloroaniline, 3-chloro-4-aminotrifluorobenzene, p-trifluoromethylaniline, and 2,4, 6-tribromoaniline.
6. The method of claim 5, wherein the 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 the target product.
7. A method according to claim 3, characterized in that said method comprises:
in S1, 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 methyl 4-bromomethylbenzoate is 10-30 mL; and/or 4-bromomethyl benzoate is transferred to a constant pressure funnel after being dissolved in DMF;
and/or S2, heating is carried out through water bath, the temperature is 70-90 ℃, and the reaction time is 8-16 h; 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.
8. The method according to claim 6, wherein in S4, the drying temperature is 50-60 ℃ and the drying time is 12-24 h;
and/or in S5, the volume ratio of PE to DCM is 5:1, or the volume ratio of PE to EA is 15: 1;
and/or in S6, the dosage of ethanol is 40-50mL relative to 5mmol of 2,4, 6-trichloroaniline; the temperature of the water bath for condensing and refluxing is 70-90 ℃, and the condensing time is 2-4 h; the drying temperature of the filter cake is 50-60 ℃.
9. Use of a novel organic halogen-containing compound as claimed in any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof in the manufacture of an anti-cancer medicament.
10. Use of a novel organic halogen-containing compound as claimed in any one of claims 4 to 8 in the preparation of an anti-cancer medicament.
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| CN107501307A (en) * | 2017-09-25 | 2017-12-22 | 上饶师范学院 | 4 (double (4 carboxybenzyl) amino of N, N ') benzene sulfonic acid eutectic Zn complexes and preparation method thereof |
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| CN102030700A (en) * | 2009-09-30 | 2011-04-27 | 中国医学科学院药物研究所 | Benzamide carboxylic acid compound as well as manufacturing method and medicinal application thereof |
| CN107501307A (en) * | 2017-09-25 | 2017-12-22 | 上饶师范学院 | 4 (double (4 carboxybenzyl) amino of N, N ') benzene sulfonic acid eutectic Zn complexes and preparation method thereof |
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