CN110003021B - Preparation method of quaternary ammonium salt dichloroacetate with anti-leukemia activity - Google Patents
Preparation method of quaternary ammonium salt dichloroacetate with anti-leukemia activity Download PDFInfo
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Abstract
The invention discloses a preparation method of quaternary ammonium dichloroacetate with leukemia resisting activity; reacting tri-n-octylamine with excessive p-dibenzyl bromide to obtain mono-substituted p-dibenzyl bromide quaternary ammonium salt; and (3) reacting the mono-substituted p-dibenzyl bromide quaternary ammonium salt with potassium dichloroacetate to obtain quaternary ammonium dichloroacetate. The in vitro cancer cell inhibition test of the compound shows that the compound has good inhibitory activity on blood disease cells, is expected to be developed into an anti-leukemia drug, and has good application prospect.
Description
Technical Field
The invention relates to a preparation method of quaternary ammonium dichloroacetate with leukemia resisting activity.
Background
The lipophilic cation utilizes the characteristic that the mitochondrial membrane potential of cancer cells is obviously higher than that of normal mitochondria, shows the toxicity of mitochondria under a certain concentration, and has high targeting property and small toxic and side effects. Dichloroacetate is easily hydrolyzed in cancer cell bodies to generate dichloroacetic acid, and the dichloroacetic acid has glycolytic inhibition capacity. One of the biggest characteristics of cancer cells from normal cells is that cancer cells tend to be powered by glycolysis, so that the combination of the lipophilic cation and dichloroacetate is expected to produce better anticancer activity.
Disclosure of Invention
The invention aims to provide quaternary ammonium dichloroacetate with leukemia resisting activity and a preparation method thereof.
In order to achieve the purpose, the invention adopts the following technical scheme:
a quaternary ammonium salt dichloroacetate compound with anti-leukemia activity has a structural formula as follows:
the preparation method of the quaternary ammonium salt dichloroacetate with the leukemia resisting activity comprises the steps of reacting tri-n-octylamine with excessive p-dibenzyl bromide to obtain mono-substituted p-dibenzyl bromide quaternary ammonium salt; and (3) reacting the mono-substituted p-dibenzyl bromide quaternary ammonium salt with potassium dichloroacetate to obtain quaternary ammonium dichloroacetate.
The synthesis equation is as follows:
the method specifically comprises the following steps:
1) synthesis of mono-substituted p-dibenzyl bromide quaternary ammonium salt: dissolving p-dibenzyl bromide in chloroform in a three-neck flask, and adding tri-n-octylamine
Dissolving in chloroform, transferring into constant pressure dropping funnel. Slowly dripping the liquid in the constant-pressure dropping funnel into a three-mouth bottle, performing reflux reaction to obtain colorless clear liquid, and removing the solvent under reduced pressure to obtain colorless viscous liquid; by CH2Cl2After dissolving, carrying out silica gel column chromatography purification to obtain colorless viscous liquid, namely the mono-substituted p-dibenzyl bromide quaternary ammonium salt 1.
2) Synthesis of quaternary ammonium salt dichloroacetate: using CHCl for the mono-substituted p-dibenzyl bromide quaternary ammonium salt synthesized in the step 1)3Dissolving, heating to reflux, adding potassium dichloroacetate (preferably potassium dichloroacetate which is 5 times of the stoichiometric amount of the mono-substituted p-dibenzyl bromide quaternary ammonium salt), stirring for reaction to obtain colorless clear liquid, and stopping the reaction. Removing solvent under reduced pressure to obtain colorless viscous liquid, dissolving with dichloromethane, performing silica gel column chromatography, and purifying with CH2Cl2And ethanol is used as eluent to obtain colorless viscous liquid, and the required product quaternary ammonium salt dichloroacetate 2 is obtained.
The invention has the following remarkable advantages: the compound with the leukemia resisting activity prepared by the invention has simple synthesis steps and clear structure, and has good inhibition effect on leukemia cells. The compound contains two pharmacophores of quaternary ammonium salt and dichloroacetate, can enter mitochondria of cancer cells in a targeted mode and inhibit glycolysis activity of the cancer cells, so that the compound synthesized by the invention has good anticancer activity and higher application prospect in developing anti-leukemia drugs.
Detailed Description
In order to make the present invention more comprehensible, the technical solutions of the present invention are further described below with reference to specific embodiments, but the present invention is not limited thereto.
Example 1: synthesis of mono-substituted p-dibenzyl bromide quaternary ammonium salt
To a 100mL three-necked flask, 1.0g (4 mmol) of p-dibenzylbromide (trade name α, α' -dibromo-p-xylene) was added and dissolved in 30mL of chloroform. 435ul (1 mmol) of tri-n-octylamine was dissolved in 5ml of chloroform, transferred to a constant pressure funnel, and slowly added dropwise to a three-necked flask. Reacting for 6h to obtain colorless clear liquid, and distilling under reduced pressure to remove the solvent to obtain colorless viscous liquid. Adding appropriate amount of CH into colorless viscous liquid2Cl2Dissolving, purifying with silica gel column, and purifying with CH2Cl2And ethanol as an eluent (v/v =50:1 → 10:1), and the gradient elution is carried out to obtain 438.5mg of colorless viscous liquid, namely the compound 1, and the characterization data are as follows:
the yield is 71.1%;1H NMR (400MHz, CDCl3) δ: 7.59 (d,J = 7.7 Hz, 2H, Ar-H), 7.50 (d, J = 7.8 Hz, 2H, Ar-H), 5.02 (s, 2H, ArCH2Br), 4.51(s, 2H, ArCH2N), 3.32 (t, 6H, 3×NCH 2C7H15), 1.77 (m, 6H, 3×NCH2CH 2C6H13), 1.28 (m, 30H, 3×NC2H4C5 H 10CH3), 0.89 (t, J = 7.0, 9H, 3×NC7H14CH 3)； HRMS, m/z 536.3826(M-Br)+theoretical value (M-Br)+ 536.3831。
Example 2: synthesis of quaternary ammonium salt dichloroacetate
A50 mL three-necked flask was charged with the mono-substituted quaternary ammonium p-dibenzylbromide salt of the compound synthesized in example 1 (100mg, 0.186mmol) and15mL of chloroform, 5mL of water, a catalytic amount of TBEA, heated to reflux. Then 155mg of potassium dichloroacetate (0.93mmol) was added and the reaction was stirred under reflux for 5d to give a colorless clear liquid. Removing solvent under reduced pressure to obtain colorless viscous liquid, adding appropriate amount of CH2Cl2Dissolving, purifying with silica gel column, and purifying with CH2Cl2And ethanol is used as an eluent (v/v =50:1 → 10:1), and the mixture is subjected to gradient elution to obtain colorless viscous liquid, namely the compound 2, which is called as the quaternary ammonium dichloroacetate for short in the invention. Product characterization data were as follows:
yield 74.5%;1H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 7.5 Hz, 2H, Ar-H), 7.20 (d, J = 7.5 Hz, 2H, Ar-H), 5.95 (s, 1H, Cl2CHCOO), 4.70 (s, 2H, ArCH2N), 4.62 (s, 2H,ArCH2OCO), 3.17 – 3.00 (t,J = 8.1 Hz, 6H, 3×NCH 2C7H15), 1.75 (m, 6H, 3×NCH2CH 2C6H13), 1.39 – 1.28 (m, 30H, 3×C5 H 10CH3), 0.91 (t, J = 6.4 Hz, 9H, 3×NC7H14CH 3)；13C NMR (101 MHz, CDCl3) δ 145.52, 132.07, 127.84, 125.25, 58.28, 31.62, 29.05, 26.31, 22.28, 14.05； HRMS, m/z: 584.4001 (M-Br)+(ii) a Theoretical value (M-Br)+ 584.3996。
Example 3: experiment for inhibiting leukemia cell proliferation by quaternary ammonium salt dichloroacetate
Quaternary ammonium salt dichloroacetate is used as a test drug, and the drug is dissolved by DMSO.
Adjusting the density of leukemia cells to 2.0 × 105Perml, 50. mu.L per well, 3 replicate wells in parallel, seeded in 96 well plates. The drug-treated groups were added with different concentrations (0.63. mu.M-40. mu.M) of the quaternary ammonium dichloroacetate prepared in example 2, the control group was added with the DMSO cell culture medium containing the same amount as the highest concentration group, and the blank control group was added with 50. mu.L of the cell culture medium per well. After incubation at 37 ℃ in a saturated humidity, 5% CO2 incubator for 48h, 10. mu.L of MTT solution (5 mg/mL) was added,after 4h incubation, the reaction was stopped, 100. mu.L DMSO was added to each well, shaken on a microplate reader for 10 min, and the absorbance value (A value) was measured at 490nm for each well. And drawing a drug dose-effect relationship curve by taking the drug concentration as an abscissa and the cell proliferation inhibition rate as an ordinate. The IC50 values were calculated by linear regression of drug concentration versus inhibition. The results are shown in Table 1.
TABLE 1 half inhibitory concentration of Quaternary ammonium salt Dichloroacetate on leukemia cells
| Cell | CA46 | Nalm6 | BALL-1 | Molt-4 | Jurkat |
| IC50(μM) | 0.85±0.11 | 1.21±0.01 | 0.25±0.05 | 1.75±0.04 | 2.49±0.37 |
The result shows that the quaternary ammonium salt dichloroacetate has high anticancer activity on leukemia cells.
In general, the quaternary ammonium salt dichloroacetate has good anticancer activity and higher market potential for developing anticancer drugs. The above description is only a preferred embodiment of the present invention, and all equivalent changes and modifications made within the scope of the present invention should be covered by the present invention.
Claims (6)
1. A quaternary ammonium salt dichloroacetate compound with leukemia resisting activity has the following structural formula:
2. a process for the preparation of quaternary ammonium dichloroacetate having antileukaemic activity according to claim 1, wherein: carrying out substitution reaction on tri-n-octylamine and p-dibenzyl bromide to obtain mono-substituted p-dibenzyl bromide quaternary ammonium salt; and performing substitution reaction on the mono-substituted p-dibenzyl bromide quaternary ammonium salt and potassium dichloroacetate to obtain quaternary ammonium salt dichloroacetate.
3. The method for preparing dichloroacetate of quaternary ammonium salt with leukemia resisting activity as claimed in claim 2, wherein: the method specifically comprises the following steps:
1) synthesis of mono-substituted p-dibenzyl bromide quaternary ammonium salt: dissolving p-dibenzyl bromide in trichloromethane in a three-neck bottle, and dissolving tri-n-octylamine in trichloromethane and transferring into a constant-pressure dropping funnel; slowly dripping the liquid in the constant-pressure dropping funnel into a three-mouth bottle, performing reflux reaction to obtain colorless clear liquid, and removing the solvent under reduced pressure; obtaining a colorless viscous liquid from CH2Cl2Dissolving, purifying by silica gel column chromatography, and purifying with CH2Cl2And ethanol is used as an eluent to obtain colorless viscous liquid, namely mono-substituted p-dibenzyl bromide quaternary ammonium salt;
2) synthesis of quaternary ammonium salt dichloroacetate: using CHCl for the mono-substituted p-dibenzyl bromide quaternary ammonium salt prepared in the step 1)3Dissolving, heating to reflux, adding potassium dichloroacetate, stirring to obtain colorless clear liquid, stopping reaction,removing the solvent under reduced pressure using CH2Cl2Dissolving, purifying with silica gel column chromatography, and purifying with CH2Cl2And ethanol is used as eluent to obtain colorless viscous liquid, namely the product of quaternary ammonium salt dichloroacetate.
4. The method for preparing dichloroacetate as quaternary ammonium salt with leukemia resisting activity as claimed in claim 3, wherein: adding potassium dichloroacetate with the stoichiometric amount being 5 times of that of the mono-substituted p-dibenzyl bromide quaternary ammonium salt.
5. Use of the quaternary ammonium salt dichloroacetate having anti-leukemia activity of claim 1 for the manufacture of a medicament for the treatment of cancer, wherein: the cancer cells are selected from Burrkit lymphoma leukemia cells, acute B-lymphocyte leukemia cells, or acute T-lymphocyte leukemia cells.
6. Use according to claim 5, characterized in that: the Burrkit lymphoma leukemia cell is CA46, the acute B lymphocyte leukemia cell is Nalm-6 or BALL-1, and the acute T lymphocyte leukemia cell is Molt-4 or Jurkat.
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| CN105017042A (en) * | 2015-07-13 | 2015-11-04 | 福建医科大学附属协和医院 | Preparation methods for anthraquinone and naphthoquinone quaternary ammonium salts with leukemia resisting function |
| CN105859777A (en) * | 2016-05-10 | 2016-08-17 | 福州大学 | Glycolysis inhibitor group contained aloe-emodin season phosphate salt and preparation method thereof |
| CN105924364A (en) * | 2016-05-10 | 2016-09-07 | 福州大学 | Aloe-emodin quaternary ammonium salt alkyl iodoacetates with multiple-related anti-cancer mechanism |
| CN107698635A (en) * | 2017-10-31 | 2018-02-16 | 华中科技大学 | A kind of anthracycline compound of dichloroacetic acid modification and its preparation method and application |
| CN109422652A (en) * | 2017-09-01 | 2019-03-05 | 南京大学 | Application of the salicylic derivative of chloroethene acyloxy in drug |
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Patent Citations (5)
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| CN105017042A (en) * | 2015-07-13 | 2015-11-04 | 福建医科大学附属协和医院 | Preparation methods for anthraquinone and naphthoquinone quaternary ammonium salts with leukemia resisting function |
| CN105859777A (en) * | 2016-05-10 | 2016-08-17 | 福州大学 | Glycolysis inhibitor group contained aloe-emodin season phosphate salt and preparation method thereof |
| CN105924364A (en) * | 2016-05-10 | 2016-09-07 | 福州大学 | Aloe-emodin quaternary ammonium salt alkyl iodoacetates with multiple-related anti-cancer mechanism |
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