CN110903338A - Sulfur-containing urea arsenic sugar with antitumor activity and preparation method and application thereof - Google Patents
Sulfur-containing urea arsenic sugar with antitumor activity and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to the field of arsenic sugar, in particular to thiourea-containing arsenic sugar with antitumor activity and a preparation method and application thereof, wherein the thiourea-containing arsenic sugar is two compounds, namely 1- (N- (4 '- (1', 3 ', 2' -dithiaarsoapentan-2-yl) phenyl) -thiourea) -2,3,4, 6-O-acetyl- β -D-glucose and 1- (N- (4 '- (1', 3 ', 2' -dithiaarsoan-2-yl) phenyl) -thiourea) -2,3,4, 6-O-acetyl- β -D-glucose.
Description
Technical Field
The invention relates to the field of arsenic sugar, and in particular relates to thiourea-containing arsenic sugar with anti-tumor activity and a preparation method and application thereof.
Background
Arsenic sugar has good antitumor activity, 2-aminoglucose and derivatives thereof, which are derivatives of chitosan, are utilized to reduce the toxicity of organic arsenic compounds, 1,3,4, 6-O-acetyl-2-amino-D-glucose has obvious effect of reducing the toxicity of organic arsenic, arsanilic acid is used as a raw material, sulfur dioxide reduction is carried out, hydrochloric acid is used for forming salt, alkalization is carried out, an upper protecting group is used for preparing a raw material, hydrochloric acid is used for forming salt, alkalization is carried out, the upper protecting group is used for preparing 4- (1,3, 2-dithioarsine) aniline, then the aniline and propargylic acid are used for generating N- (4- (1,3, 2-dithioarsine) phenyl) alkynoyl gum under the action of N, N' -cyclohexyl carbodiimide, 2-azide-1, 3,4, 6-0-acetyl-D-glucose and N- (4- (1,3, 2-dithioarsine) phenyl) alkynylamide to generate N- (4 ' -arsenoxyphenyl) -1- (1 ', 3 ', 4',6' -0-acetyl-D-glucose) -1,2, 3-triazole-4-formamide, reacting the obtained product with 1, 2-ethanedithiol to obtain the 1,3,4, 6-O-acetyl-D-glucose arsenic sugar derivative, and further researching to find that the 1,2, 3-triazole ring constructed by click reaction does not enhance the anti-tumor effect of arsenic sugar. This suggests that other derivatives of linking organic arsenic and sugars may also be used.
The method has long route and low yield, and the intermediate undergoes the processes of organic arsenic deprotection and protecting group reapplication, the organic arsenic sugar after deprotection is easy to oxidize in the purification process, and the yield is reduced due to polymerization, and the target compound obtained by adopting the scheme is a mixture of α and β.
Disclosure of Invention
The invention provides thiourea-containing arsenic sugar with antitumor activity, a preparation method and application thereof, aiming at the defects that the reaction route for preparing arsenic sugar is long, the total yield is low, and the product is a mixture of α and β, the method utilizes the electrophilicity of sulfur isocyanate to attack the protected derivative of p-aminophenylarsenous acid, has simple reaction operation and high yield, can obtain the specific thiourea-containing arsenic sugar with a stereo configuration (namely, a specific β configuration product is formed at room temperature), has the thiourea-containing structure in the compound to inhibit the urea circulation in tumor metabolism, and can efficiently construct the specific arsenic sugar with the stereo configuration.
In order to achieve the purpose, the invention designs a thiourea arsenic-containing sugar with antitumor activity, which is characterized in that: the thiourea-containing arsenic sugar has a structural formula as follows:
wherein R is
Two compounds, 1- (N- (4 '- (1', 3 ', 2' -dithiaarsenopan-2-yl) phenyl) -thiourea) -2,3,4, 6-O-acetyl- β -D-glucose (I) and 1- (N- (4 '- (1', 3 ', 2' -dithiaarsenahexan-2-yl) phenyl) -thiourea) -2,3,4, 6-O-acetyl- β -D-glucose (II), are formed, respectively, of the formula:
is that
The invention also provides a preparation method of the thiourea-containing arsenic sugar with anti-tumor activity, which comprises the following steps:
1) 4-aminophenylarsenous acid is taken as a raw material, reduced by sulfur dioxide gas, chlorinated by hydrochloric acid to para-dichloroarsenaniline hydrochloride, added with ammonia water for alkalization at the temperature of 0-25 ℃, the precipitated solid is filtered and dried to prepare 4-aminophenylarsenous acid, dissolved in methanol or ethanol solution,
2) reacting 4-aminophenylarsenous acid with 1, 2-ethanedithiol/1, 3-propanedithiol to precipitate solid, filtering and drying to obtain 4- (1,3, 2-dithiaarsane-2-yl) aniline or 4- (1,3, 2-dithiaarsane-2-yl) aniline;
3) dissolving 1-bromo-2, 3,4, 6-O-acetyl- α -D-glucose in an organic solvent, substituting bromine at the outmost position of 1-bromo-2, 3,4, 6-O-acetyl- α -D-glucose with potassium sulfoisocyanate under the action of a 4A molecular sieve and tetrabutylammonium bromide (phase transfer catalyst), refluxing for 4-6h at the temperature of 60-80 ℃, filtering, concentrating under reduced pressure, and performing column chromatography separation to obtain 1-isothiocyanato-2, 3,4, 6-O-acetyl- β -D-glucose;
4) placing 1-isothiocyanic-2, 3,4, 6-O-acetyl- β -D-glucose and 4- (1,3, 2-dithiaarsoalin-2-yl) aniline/4- (1,3, 2-dithiaarsoalin-2-yl) aniline in a solvent, stirring for 2-5h at room temperature, after the reaction is finished, evaporating the solvent under reduced pressure, and carrying out column chromatography separation and drying to obtain 1- (N- (4 '- (1', 3 ', 2' -dithiaarsoalin-2-yl) phenyl) -thiourea) -2,3,4, 6-O-acetyl- β -D-glucose (I) or 1- (N- (4 '- (1', 3 ', 2' -dithiaarsoalin-2-yl) phenyl) -thiourea) -2,3,4, 6-O-acetyl- β -D-glucose (II).
Further, in the step 1), the solvent used in the preparation of p-arsenic dichloride aniline hydrochloride is one of methanol or acetonitrile, and the reaction temperature is room temperature.
The solvent used in the process of preparing the 4-aminophenylarsenous acid is one of water or acetonitrile, and the concentration of ammonia water is 2-13 mol/L.
Still further, in the step 2), the molar ratio of 4-aminophenylarsenous acid to 1, 2-ethanedithiol to 1, 3-propanedithiol is 1: 1-1.5; the reaction time was 4 h.
In the step 3), the organic solvent is anhydrous acetonitrile or anhydrous N, N-dimethylformamide, nucleophilic substitution occurs in the reaction, and the acetyl ortho-group at the ortho-position of the anomeric position participates in the effect to cause the anomeric position nucleophilic substitution to generate a product with β configuration.
In the step 4), the solvent is anhydrous acetonitrile or dichloromethane, and the molar ratio of 1-isothiocyanato-2, 3,4, 6-O-acetyl- β -D-glucose to 4- (1,3, 2-dithiaarsapen-2-yl) aniline/4- (1,3, 2-dithiaarsapen-2-yl) aniline is 1: 1-3.
The invention also provides application of the thiourea-containing arsenic sugar in preparation of anti-liver cancer drugs and anti-breast cancer drugs.
The preparation routes of the compounds (I) and (II) of the present invention are as follows:
a route for the preparation of 1- (N- (4' - (1",3", 2 "-dithiaarsoalin-2-yl) phenyl) -thiourea) -2,3,4, 6-O-acetyl- β -D-glucose (I) is as follows:
a route for the preparation of 1- (N- (4' - (1",3", 2 "-dithiaarsanilide-2-yl) phenyl) -thiourea) -2,3,4, 6-O-acetyl- β -D-glucose (II) is as follows:
the invention has the beneficial effects that:
the invention has simple reaction operation and higher yield; meanwhile, the thiourea arsenic-containing sugar with specific stereo configuration can be obtained, and has good antitumor activity.
Detailed Description
The present invention is described in further detail below with reference to specific examples so as to be understood by those skilled in the art.
Example 1
Preparation of 1- (N- (4' - (1",3", 2 "-dithiaarsoalin-2-yl) phenyl) -thiourea) -2,3,4, 6-O-acetyl- β -D-glucose (I):
1) preparation of 4-aminophenylarsenous acid
a. Weighing 4-aminobenzene arsenic acid (5g,23mmol) and potassium iodide (25mg,0.15mmol) and dissolving in a mixed solution of methanol/concentrated hydrochloric acid (30mL/24mL), cooling to 0 ℃, and introducing SO2Gas was allowed to flow for 30min until the solution changed from orange-red to light yellow. The solution was allowed to stand overnight at 0 ℃ in a refrigerator, filtered, and the filter cake was washed twice with 25mL of cold diethyl ether to give 4-dichloroarsenious aniline hydrochloride (6.2g, 93.7%);
dissolving 4-dichloroarsenious aniline hydrochloride (6.2g, 93.7%) in 150mL of aqueous solution, cooling to 0-5 ℃, adding 10 mol/L concentrated ammonia water in batches, stirring for 30 minutes in 26mL, separating out a white solid, standing the solution at 0-5 ℃ overnight, filtering, washing a filter cake twice with 5mL of distilled water, and drying overnight in vacuum to obtain white 4-aminophenylarsenious acid;
2) preparation of 4- (1,3, 2-dithiaarsoalin-2-yl) aniline:
4-Aminophenylarsenious acid (2g,10.9266mmol) was dissolved in 20mL of ethanol solution, and 1, 2-ethanedithiol (1.121g,11.9099mmol) was added thereto at room temperature, stirred for 4 hours, filtered, and dried to obtain 4- (1,3, 2-dithiaarsenopan-2-yl) aniline (1.557g, yield: 55%) as a white solid;
3) preparation of 1-isothiocyanato-2, 3,4, 6-O-acetyl- β -D-glucose:
stirring potassium isothiocyanate (583mg,6.0mmol) in tetrabutylammonium bromide (967mg,3.0mmol), 4A molecular sieve (4.5g) and 140mL anhydrous acetonitrile at room temperature under the protection of nitrogen for 3 hours, adding 10mL anhydrous acetonitrile solution of 1-bromo-2, 3,4, 6-O-acetyl- α -D-glucose (1233.6mg,1.0mmol) into the solution, heating for reaction for 3 hours, cooling to room temperature, filtering, evaporating the solvent from the filtrate under reduced pressure, and performing column chromatography to obtain a white foamy solid, namely 1-isothiocyanato-2, 3,4, 6-O-acetyl- β -D-glucose (0.9234g, 79.05%);
4) preparation of 1- (N- (4 '- (1', 3 ', 2' -Diazaarsapen-2-yl) phenyl) -thiourea) -2,3,4, 6-O-acetyl- β -D-glucose (I)
1-isothiocyanato-2, 3,4, 6-O-acetyl- β -D-glucose (200mg,0.5136mmol),4- (1,3, 2-dithiaoarsenopentan-2-yl) aniline (134mg,0.5136mmol) and anhydrous dichloromethane (10mL) were weighed, heated under reflux and stirred for 4 hours to complete the reaction, and the solution after the reaction was subjected to reduced pressure distillation with a rotary evaporator to remove the solvent, followed by column chromatography (eluent petroleum ether: ethyl acetate: 4:1) to give 1- (N- (4' - (1",3", 2 "-dithiarsenopentan-2-yl) phenyl) -thiourea) -2,3,4, 6-O-acetyl- β -D-glucose (I) (273.6mg, yield: 81.9%).
The product, namely 1- (N- (4 '- (1', 3 ', 2' -dithiaarsapen-2-yl) phenyl) -thiourea) -2,3,4, 6-O-acetyl- β -D-glucose (I) is subjected to1H NMR、13CNMR and HR-MS characterization:
1H NMR(400MHz,Chloroform-d)δ7.92(s,1H),7.66(d,J＝8.3Hz,2H),7.10(d,J＝8.2Hz,2H),6.56(d,J＝8.7Hz,1H),5.72(t,J＝9.1Hz,1H),5.28(t,J＝9.5Hz,1H),4.97(t,J＝9.7Hz,1H),4.84(t,J＝9.6Hz,1H),4.26(dd,J＝12.5,4.6Hz,1H),4.03(d,J＝14.3Hz,1H),3.80(s,1H),3.45–3.24(m,2H),3.24–2.97(m,2H),1.97(dd,J＝19.8,7.9Hz,12H).
13C NMR(101MHz,Chloroform-d)δ181.05,169.96,169.64,168.80,168.57,142.76,134.86,131.51,123.79,82.25,72.66,71.59,69.50,67.15,60.56,41.01,19.77,19.67,19.57.
HRMS：M+H+: C23H30AsN2O9S3, theoretical: 649.0324, found: 649.0306.
example 2
Preparation of 1- (N- (4' - (1",3", 2 "-dithiaarsanilide-2-yl) phenyl) -thiourea) -2,3,4, 6-O-acetyl- β -D-glucose (II):
1) preparation of 4-aminophenylarsenous acid
a. Weighing 4-aminobenzene arsenic acid (5g,23mmol) and potassium iodide (25mg,0.15mmol) and dissolving in a mixed solution of methanol/concentrated hydrochloric acid (30mL/24mL), cooling to 0 ℃, and introducing SO2Gas was allowed to flow for 30min until the solution changed from orange-red to light yellow. The solution was allowed to stand overnight at 0 ℃ in a refrigerator, filtered, and the filter cake was washed twice with 25mL of cold diethyl ether to give 4-dichloroarsenious aniline hydrochloride (6.2g, 93.7%);
dissolving 4-dichloroarsenious aniline hydrochloride (6.2g, 93.7%) in 150mL of aqueous solution, cooling to 0-5 ℃, adding 10 mol/L concentrated ammonia water in batches, stirring for 30 minutes in 26mL, separating out a white solid, standing the solution at 0-5 ℃ overnight, filtering, washing a filter cake twice with 5mL of distilled water, and drying overnight in vacuum to obtain white 4-aminophenylarsenious acid;
2) preparation of 4- (1,3, 2-Diazaarsanilide-2-yl) aniline
4-Aminophenylarsenious acid (3.3946g,18.5424mmol) was reacted directly with 1, 3-propanedithiol (2.063g,19.062mmol), refluxed in 30mL of ethanol for 2 hours, cooled to room temperature, filtered, the cake was washed with 5mL of ethanol 2 times, and dried under vacuum overnight to give 4- (1,3, 2-dithasoahexan-2-yl) aniline as a white solid (3.8994g, yield: 85.82%).
3) Preparation of 1-isothiocyanato-2, 3,4, 6-O-acetyl- β -D-glucose:
stirring potassium isothiocyanate (583mg,6.0mmol), tetrabutylammonium bromide (967mg,3.0mmol) and a 4A molecular sieve (4.5g) in 140mL anhydrous acetonitrile at room temperature under the protection of nitrogen for 3 hours, adding a 10mL anhydrous acetonitrile solution of 1-bromo-2, 3,4, 6-O-acetyl- α -D-glucose (1233.6mg,1.0mmol) into the solution, heating for reaction for 3 hours, cooling to room temperature, filtering, evaporating the solvent from the filtrate under reduced pressure, and carrying out column chromatography to obtain a white foamy solid, namely 1-isothiocyanic-2, 3,4, 6-O-acetyl- β -D-glucose (0.9234g, 79.05%);
4) preparation of 1- (N- (4' - (1",3", 2 "-dithiaarsanilide-2-yl) phenyl) -thiourea) -2,3,4, 6-O-acetyl- β -D-glucose (II):
1-isothiocyanato-2, 3,4, 6-O-acetyl- β -D-glucose (200mg,0.5136mmol),4- (1,3, 2-dithiaarsazepan-2-yl) aniline (140mg,0.5136mmol) and anhydrous dichloromethane (10mL) were weighed, stirred under reflux for 4 hours to complete the reaction, and the reaction solution was subjected to reduced pressure distillation using a rotary evaporator to remove the solvent, followed by column chromatography (eluent petroleum ether: ethyl acetate: 4:1) to give 1- (N- (4' - (1",3", 2 "-dithiaarsazepan-2-yl) phenyl) -thiourea) -2,3,4, 6-O-acetyl- β -D-glucose (II) (243.2mg, yield: 70.1%).
The product is 1- (N- (4 '- (1', 3 ', 2' -dithiaarsanilide-2-yl) phenyl) -thiourea) -2,3,4, 6-O-acetyl- β -D-glucose (II)13CNMR and HR-MS characterization.
1H NMR(400MHz,Chloroform-d)δ7.99(s,1H),7.93(d,J＝8.3Hz,2H),7.24(d,J＝8.2Hz,2H),6.69(d,J＝8.5Hz,1H),5.73(t,J＝9.0Hz,1H),5.30(t,J＝9.5Hz,1H),4.98(t,J＝9.7Hz,1H),4.86(t,J＝9.6Hz,1H),4.30(dd,J＝12.5,4.6Hz,1H),4.11–3.96(m,1H),3.89–3.72(m,1H),2.87–2.72(m,2H),2.71–2.58(m,2H),2.21–2.04(m,2H),1.98(dd,J＝20.2,9.6Hz,12H).
13C NMR(101MHz,Chloroform-d)δ181.12,170.04,169.63,168.78,168.59,137.78,134.85,133.33,124.56,82.32,72.68,71.56,69.48,67.18,60.57,27.06,24.77,24.71,19.78,19.68,19.57.
HRMS：M+H+: theoretical value of C24H32AsN2O9S 3: 663.0480, found: 663.0461.
it can be seen from the following experiments that compounds I and II have good biological activities against liver cancer and breast cancer:
EXAMPLE 3 Effect of the inhibition Effect of the above-mentioned Compounds I and II on hepatoma cell HepG2
The experimental method comprises the following steps:
1. diluting liver cancer cell HepG2 to 1 × 106Perml cell suspension, 100uL was inoculated into 96-well plates
2. After the cells adhered, the medium (DMEM, 10% FBS) was aspirated, compound I or II at different concentrations was added to a 96-well plate (medium dilution), and culture was continued for 48 h.
3. 10uL (5mg/mL) MTT solution (PBS dilution) was added to each well and incubation was continued for 4h
4. Aspirate the medium and add 150uL DMSO per well
5. Shaking for 10min on shaking table, and detecting absorbance at 490nm with enzyme labeling instrument
6. Cell viability ═ experimental group)/blank group (blank group: no drug added), triplicate per group, and IC calculated50。
A compound I: IC (integrated circuit)507.62 ± 0.10 μ M, compound II: IC (integrated circuit)50＝2.81±0.03μM。
In conclusion, the compounds I and II have good inhibition effect on liver cancer cells HepG 2.
EXAMPLE 4 Effect of the inhibitory Effect of the above-mentioned Compounds I and II Breast cancer cells Hela
The experimental method comprises the following steps:
1. diluting Hela cells of breast cancer to 1 × 106Perml cell suspension, 100uL was inoculated into 96-well plates
2. After the cells adhered, the medium (DMEM, 10% FBS) was aspirated, compound I or II at different concentrations was added to a 96-well plate (medium dilution), and culture was continued for 48 h.
3. 10uL (5mg/mL) MTT solution (PBS dilution) was added to each well and incubation was continued for 4h
4. Aspirate the medium and add 150uL DMSO per well
5. Shaking for 10min on shaking table, and detecting absorbance at 490nm with enzyme labeling instrument
6. Cell viability ═ experimental group)/blank group (blank group: no drug added), triplicate per group, and IC calculated50。
A compound I: IC (integrated circuit)5014.4 ± 0.23 μ M, compound II: IC (integrated circuit)50＝11.05±0.17μM。
In conclusion, the compounds I and II have good inhibition effect on breast cancer cell Hela.
Other parts not described in detail are prior art. Although the present invention has been described in detail with reference to the above embodiments, it is only a part of the embodiments of the present invention, not all of the embodiments, and other embodiments can be obtained without inventive step according to the embodiments, and the embodiments are within the scope of the present invention.
Claims (8)
1. A thiourea-containing arsenic saccharide having an antitumor activity, characterized in that: the thiourea-containing arsenic sugar has a structural formula as follows:
wherein R is
2. A process for preparing thiourea-containing arsenic suzus having antitumor activity according to claim 1, wherein: the method comprises the following steps:
1) the method comprises the following steps of (1) taking 4-aminophenylarsenic acid as a raw material, reducing the raw material by sulfur dioxide gas, chlorinating p-dichloroarsenaniline hydrochloride by hydrochloric acid, adding ammonia water for alkalization at the temperature of 0-25 ℃, filtering and drying precipitated solids to prepare 4-aminophenylarsenous acid, and dissolving the 4-aminophenylarsenous acid in a methanol or ethanol solution for later use;
2) reacting 4-aminophenylarsenous acid with 1, 2-ethanedithiol/1, 3-propanedithiol to precipitate solid, filtering and drying to obtain 4- (1,3, 2-dithiaarsane-2-yl) aniline or 4- (1,3, 2-dithiaarsane-2-yl) aniline;
3) dissolving 1-bromo-2, 3,4, 6-O-acetyl- α -D-glucose in an organic solvent, substituting bromine at the anomeric position of 1-bromo-2, 3,4, 6-O-acetyl- α -D-glucose with potassium thioisocyanate under the action of a 4A molecular sieve and tetrabutylammonium bromide, refluxing for 4-6h at the temperature of 60-80 ℃, filtering, concentrating under reduced pressure, and separating by column chromatography to obtain 1-isothiocyanato-2, 3,4, 6-O-acetyl- β -D-glucose;
4) placing 1-isothiocyanic-2, 3,4, 6-O-acetyl- β -D-glucose and 4- (1,3, 2-dithiaarsoalin-2-yl) aniline/4- (1,3, 2-dithiaarsoalin-2-yl) aniline in a solvent, stirring for 2-5h at room temperature, after the reaction is finished, evaporating the solvent under reduced pressure, and carrying out column chromatography separation and drying to obtain thiourea-containing arsenic sugar with antitumor activity, wherein the thiourea-containing arsenic sugar is 1- (N- (4 '- (1', 3 ', 2' -dithiaarsoalin-2-yl) phenyl) -thiourea) -2,3,4, 6-O-acetyl- β -D-glucose (I) or 1- (N- (4 '- (1', 3 ', 2' -dithiaarsoalin-2-yl) phenyl) -thiourea) -2,3,4, 6-O-acetyl- β -D-glucose (II).
3. The method for producing thiourea-containing arsenic sugar having antitumor activity as claimed in claim 2, wherein: in the step 1), the solvent used in the process of preparing the p-arsenic dichloride aniline hydrochloride is one of methanol or acetonitrile, and the reaction temperature is room temperature.
4. The method for producing thiourea-containing arsenic sugar having antitumor activity as claimed in claim 2, wherein: in the step 1), the solvent used in the process of preparing the 4-aminophenylarsenous acid is one of water or acetonitrile, and the concentration of ammonia water is 2-13 mol/L.
5. The method for producing thiourea-containing arsenic sugar having antitumor activity as claimed in claim 2, wherein: in the step 2), the molar ratio of 4-aminophenylarsenous acid to 1, 2-ethanedithiol to 1, 3-propanedithiol is 1: 1-1.5; the reaction time was 4 h.
6. The method for producing thiourea-containing arsenic sugar having antitumor activity as claimed in claim 2, wherein: in the step 3), the organic solvent is anhydrous acetonitrile or anhydrous N, N-dimethylformamide.
7. The method for producing thiourea-containing arsenose having antitumor activity according to claim 2, wherein the solvent used in the step 4) is anhydrous acetonitrile or dichloromethane, and the molar ratio of 1-isothiocyanato-2, 3,4, 6-O-acetyl- β -D-glucose to 4- (1,3, 2-dithiaarsoalin-2-yl) aniline/4- (1,3, 2-dithiaarsoalin-2-yl) aniline is 1: 1-3.
8. Use of the thiourea containing arsenic saccharide of claim 1 in the preparation of an anti-liver cancer drug and an anti-breast cancer drug.
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