CN109369724B - Organic arsenic compound and application thereof - Google Patents

Organic arsenic compound and application thereof Download PDF

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CN109369724B
CN109369724B CN201811246044.7A CN201811246044A CN109369724B CN 109369724 B CN109369724 B CN 109369724B CN 201811246044 A CN201811246044 A CN 201811246044A CN 109369724 B CN109369724 B CN 109369724B
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CN109369724A (en
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房建国
宋子龙
张军民
刘亚萍
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Lanzhou University
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Abstract

The invention discloses an organic arsenic compound, which has the following structural formula:
Figure DDA0001837686520000011
wherein n is 1 or 2, R, R1、R2、R3、R4、R5Each independently is amino, R6‑CO‑NH‑、R7-CO-O-, alkyl, aryl, heterocyclic substituent, alkoxy, alkylamino, halogen atom, nitro, hydroxyl or hydrogen atom; said R6Is alkyl, aminoalkyl or aryl; said R7Is alkyl, aminoalkyl or aryl. The organic arsenic compound has good inhibitory activity on thioredoxin reductase and strong cytotoxicity on tumor cells HL-60, and can be used for preparing thioredoxin reductase inhibitors or antitumor drugs taking the thioredoxin reductase as a target.

Description

Organic arsenic compound and application thereof
Technical Field
The invention belongs to the field of medicines, and particularly relates to an organic arsenic compound and application thereof.
Background
Arsenic is widely distributed on earth as a semi-metallic or non-metallic element, and most of arsenic is present in sulfur-containing or metal-containing minerals. Arsenic-based molecules have been used as pharmacotherapeutic agents for centuries, e.g., for the treatment of psoriasis, leukemia, syphilis, rheumatism, and the like. However, the toxicity of arsenic compounds to human body has caused some hindrance as drugs, and until the 80 th 20 th century, clinical studies have shown that inorganic arsenic compounds, namely arsenic trioxide, can relieve the symptoms of patients with acute promyelocytic leukemia, so that arsenic has new eosin as the basis of drug molecules. The organic arsenic molecules generally contain carbon atoms that form covalent bonds with arsenic, and the diversity of organic arsenic molecules is greatly increased by the fact that carbon atoms can form different kinds of covalent bonds. In addition to structural diversity, organoarsenic molecules are generally more stable, less toxic, and more bioavailable. Based on the success of arsenic trioxide as a drug for leukemia, more and more organic arsenic compounds are being studied extensively.
Thioredoxin reductase (TrxR) is a selenoprotein that, together with NADPH and its substrate thioredoxin (Trx), constitutes the thioredoxin system, which is a highly conserved, one of the important systems that is present in almost all lives to regulate the redox homeostasis in the organism. The thioredoxin system plays a very important role in the regulation of redox signals involved in physiological processes such as cell proliferation, differentiation and death, DNA repair, angiogenesis and embryogenesis. In recent years, TrxR has received a great deal of attention due to its important role in biomedicine. Most importantly, a large number of studies show that TrxR is overexpressed in a variety of tumor types, such as non-small cell lung cancer, breast cancer, liver cancer, cervical cancer, and the like, as compared to normal tissues. These studies all indicate that TrxR plays an important role in tumorigenesis, and reveal that TrxR can serve as an important target for anti-tumor.
Combining the published research results, the applicant designs and synthesizes an organic arsenic compound with a novel structure, and researches the inhibition effect of the compound on thioredoxin reductase (TrxR) and the toxicity of the compound on tumor cells.
Disclosure of Invention
In view of the current research situation of organic arsenic compounds, the invention aims to provide an organic arsenic compound with a novel structure, and the organic arsenic compound has good inhibition effect on thioredoxin reductase.
In order to achieve the purpose, the invention provides the following technical scheme:
an organoarsenic compound having the formula:
Figure BDA0001837686510000021
wherein n is 1 or 2,
R、R1、R2、R3、R4、R5each independently is amino, R6-CO-NH-、R7-CO-O-, alkyl, aryl, heterocyclic substituent, alkoxy, alkylamino, halogen atom, nitro, hydroxyl or hydrogen atom;
said R6Is alkyl, aminoalkyl or aryl;
said R7Is alkyl, aminoalkyl or aryl.
Preferably, the carbon number of the alkyl group, alkoxy group, alkylamino group and/or aminoalkyl group is 1 to 12.
More preferably, the carbon number of the alkyl group, alkoxy group, alkylamino group and/or aminoalkyl group is 1 to 6.
Preferably, the aryl group is phenyl, alkylphenyl, nitrophenyl, hydroxyphenyl, halophenyl, naphthyl, anthracenyl, or biphenyl; the heterocyclic substituent is cycloazanyl, oxiranyl, episulfide ethyl, azetidinyl, pyrrolidinyl, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, furyl, thienyl, piperidyl, pyridyl, morpholinyl, piperazinyl, azepine, oxepin or thiazepine; the halogen atom is fluorine, chlorine, bromine or iodine.
Preferably, R is1、R2、R3、R4And R5In which at least one is amino or R6-CO-NH-。
Preferably, the organic arsenic compound has one of the following structural formulas:
formula 1:
Figure BDA0001837686510000031
formula 2:
Figure BDA0001837686510000032
formula 3:
Figure BDA0001837686510000033
formula 4:
Figure BDA0001837686510000034
formula 5:
Figure BDA0001837686510000035
wherein n is 1 or 2, x is 1-6, such as x is 1, 2, 3, 4, 5 or 6.
The organic arsenic compound is particularly preferably:
Figure BDA0001837686510000036
Figure BDA0001837686510000041
the application of the organic arsenic compound in preparing thioredoxin reductase inhibitors.
The organic arsenic compound is applied to preparation of an anti-tumor medicament, and preferably, the anti-tumor medicament is an anti-leukemia medicament.
Detailed Description
The technical solutions in the present disclosure will be described clearly and completely below, and it should be understood that the described embodiments are only a part of the embodiments of the present disclosure, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The organic arsenic compound has the following structural formula:
Figure BDA0001837686510000051
wherein n is 1 or 2,
R、R1、R2、R3、R4、R5each independently is amino, R6-CO-NH-、R7-CO-O-, alkyl, aryl, heterocyclic substituent, alkoxy, alkylamino, halogen atom, nitro, hydroxyl or hydrogen atom;
said R6Is alkyl, aminoalkyl or aryl;
said R7Is alkyl, aminoalkyl or aryl.
In the present invention, the carbon number of the alkyl group, alkoxy group, alkylamino group and/or aminoalkyl group is 1 to 12, and more preferably, the carbon number of the alkyl group, alkoxy group, alkylamino group and/or aminoalkyl group is 1 to 6.
In the present invention, the aryl group is a phenyl group, an alkylphenyl group, a nitrophenyl group, a hydroxyphenyl group, a halophenyl group, a naphthyl group, an anthracenyl group or a biphenyl group; the heterocyclic substituent is cycloazanyl, oxiranyl, episulfide ethyl, azetidinyl, pyrrolidinyl, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, furyl, thienyl, piperidyl, pyridyl, morpholinyl, piperazinyl, azepine, oxepin or thiazepine; the halogen atom is fluorine, chlorine, bromine or iodine.
The organic arsenic compound can be prepared by the following method:
Figure BDA0001837686510000061
Figure BDA0001837686510000071
the specific process comprises the following steps:
1. synthesis of Compound D:
preparing m-nitrobenzene fluoroboric acid diazonium salt: 31.5mL of concentrated hydrochloric acid and 25mL of water were mixed uniformly, and then 17.25g of m-nitroaniline was added thereto and stirred uniformly. Placing in a low-temperature reactor at 0 ℃. After cooling was complete, sodium nitrite solution (8.65g sodium nitrite in 20mL water) was added dropwise to the ice bath solution, with potassium iodide starch indicating the end point. After the diazonium salt is made, a sodium fluoroborate solution (27.5g sodium fluoroborate dissolved in 55mL water) is added dropwise to the diazonium salt solution in a low temperature reactor at 0 ℃. The reaction solution is observed to be more and more turbid and thick, the reaction is lifted after 30 minutes of reaction, suction filtration is carried out until no liquid is left, the filter cake is washed twice by ice water until no liquid is left, the filter cake is washed twice by using glacial methanol until no liquid is left, and the filter cake is washed twice by using glacial ethyl ether until no liquid is left. And (5) drying for later use.
Preparing a sodium arsenite solution: mixing 8g of sodium hydroxide and 300mL of water, clarifying, adding 26g of sodium arsenite, stirring, clarifying the solution, adding 3g of cuprous chloride, and uniformly stirring to obtain the sodium arsenite solution.
Preparation of m-nitrobenzene arsenic acid: the previously prepared diazonium fluoroborate solid was stirred well in 150mL of water. This solution was added to the sodium arsenite solution within 1 hour. After the addition, the reaction was carried out for 1 hour. Adding 50mL of 10% sodium hydroxide solution, reacting for 1 hour, placing the reaction system in 60 ℃, reacting for 30 minutes, carrying out suction filtration while the reaction is hot, washing a filter cake with water, and adjusting the pH of the filtrate with concentrated hydrochloric acid until the color of the litmus blue test paper changes. The solution was filtered with suction, the filter cake was washed with a small amount of water, activated carbon was added to the filtrate, and the mixture was concentrated to 175mL by heating. The black liquid was filtered while hot to give an almost colorless filtrate, the pH of the filtrate was adjusted with concentrated hydrochloric acid until the color of Congo red paper became just changed, and the liquid was left in a refrigerator overnight. The next morning, a large number of white flaky crystals were found to precipitate at the bottom of the flask. And (4) carrying out suction filtration to obtain a product. The product was washed with ice water and left to dry for further use. The filtrate was again concentrated to 75mL, placed in the refrigerator again overnight and filtered to give the product. And (5) drying for later use.
Preparing m-nitrobenzene arsenic oxygen: mixing m-nitrobenzene arsenic acid, methanol, concentrated hydrochloric acid and potassium iodide uniformly, and introducing SO into the solution2The solution was observed to change from white turbidity to light yellow slightly turbid, and the reaction was terminated when no iodine was formed. After the reaction, the methanol in the solution is evaporated out under reduced pressure,then the water is sucked off, the product is in yellow opaque oil, and then the product is dried for standby.
Preparing m-nitroaniline five-membered and six-membered disulfide ring: dissolving m-nitrobenzene arsenic oxide in ethanol, slowly dripping ethanedithiol or propanedithiol, refluxing for about half an hour after dripping, pressurizing, concentrating, and performing column chromatography to obtain a yellow product.
Synthesis of final product D: dissolving m-nitroaniline arsenic five-membered and six-membered disulfide rings in acetone, adding water with half volume of the acetone, stirring uniformly, adding sodium hydrosulfite, stirring, and reacting at 50 ℃ for half an hour. Extracting with ethyl acetate, concentrating, and performing column chromatography to obtain light yellow product.
2. Synthesis of compound B, C:
synthesis of amino/o-aminophenylarsenic chloride: adding 30mL of methanol, 24mL of concentrated hydrochloric acid and 100mg of potassium iodide into a 100mL round-bottom flask, uniformly stirring, adding 10.9g of p-amino phenylarsonic acid/o-amino phenylarsonic acid into the round-bottom flask, and uniformly stirring to obtain an orange clear liquid. At this moment, the sulfur dioxide generation device is put up (sodium bisulfite and concentrated sulfuric acid are used as generation raw materials, and a sodium hydroxide solution is a tail gas absorption device), sulfur dioxide is slowly introduced into the orange clear liquid, the orange color is slowly faded away along with the introduction of the sulfur dioxide, the color of the solution is gradually changed into a slightly yellowish turbid state, and along with the introduction of the sulfur dioxide, the precipitation is more and more, and the sulfur dioxide is continuously introduced until the precipitation is not generated any more. At this point, the turbid reaction solution was filtered with suction to give a white to pale yellow solid, and the filter cake was rinsed several times with diethyl ether.
② the synthesis of the amino/o-aminobenzene arsenic oxygen: adding the solid compounds into a round-bottom flask, adding a 20% ammonia water solution, adjusting the pH value to 8-9, and carrying out suction filtration on the turbid liquid to obtain an off-white solid. P-amino/o-amino benzene arsenic oxide.
Preparing five-membered and six-membered disulfide rings of p-amino/o-aminophenylarsenic: 5, adding compound D.
3. Synthesis of Compound A:
preparing m-nitro p-hydroxy-phenyl arsenic chloride: adding 30mL of methanol, 24mL of concentrated hydrochloric acid and 100mg of potassium iodide into a 100mL round-bottom flask, uniformly stirring, adding 13.2g of p-hydroxy m-nitroarsinic acid into the flask, and uniformly stirring to obtain an orange clear liquid. At the moment, a sulfur dioxide generating device is well built (sodium bisulfite and concentrated sulfuric acid are used as generating raw materials, and a sodium hydroxide solution is used as a tail gas absorption device), sulfur dioxide is slowly introduced into the orange clear liquid, the orange color slowly recedes along with the introduction of the sulfur dioxide, the color of the solution gradually changes into a light yellow and slightly turbid state, the introduction of the sulfur dioxide is continued for a period of time until the color of the reaction liquid does not change any more, and finally the color of the obtained reaction liquid is the light yellow and slightly turbid state.
② the synthesis of m-nitro-p-hydroxyphenylarsenic oxide: and at the moment, directly adjusting the pH of the reaction solution to 8-9 by using ammonia water, separating out solids which are very adhesive, continuously stirring at the moment, enabling the solids to be not adhesive and to be larger blocks of solids, crushing the larger blocks of solids by using a scraper, continuously stirring for a while, carrying out suction filtration on the solids, and rinsing the solids by using diethyl ether to finally obtain yellow solids.
Preparation of m-nitro p-hydroxyphenylarsenic five-membered and six-membered disulfide rings: 5, adding compound D.
Fourthly, preparation of a final product A: the same as that of Compound D.
4. Synthesis of compounds E, F and G:
preparation of compound G: dissolving 1.5eq of Boc protected amino acid in dry dichloromethane, stirring uniformly, adding EDCI 3eq under an ice bath condition, stirring for about 5 minutes, adding HOBT 2eq, stirring for about 5 minutes, adding compound B1 eq, stirring for half an hour under an ice bath condition, removing the ice bath, and reacting at the normal temperature overnight. The next day the reaction was quenched by addition of water, extracted with dichloromethane, and the reaction was washed with water. And combining the concentrated organic phases, directly carrying out the next reaction without purification, adding an ethyl acetate hydrochloride solution into the concentrated organic phases, monitoring the reaction by using thin-layer chromatography until the raw materials disappear, spin-drying the reaction liquid, extracting by using dichloromethane, washing by using saturated sodium bicarbonate, combining the organic phases, and carrying out column chromatography to obtain the product.
Preparation of compound E: the same procedure as for the preparation of product G, except that compound D is used instead of compound B.
Preparation of compound F: the same procedure as for the preparation of product G, except that compound C is used instead of compound B.
5. Synthesis of compounds H and I:
preparation of compound H: NHS 1eq was dissolved in dry dichloromethane and Boc protected amino acid was added (II) ((III))
Figure BDA0001837686510000101
x is 1-6)1.2eq, EDCI 1.8eq is added under the ice-bath condition, the ice-bath is removed after half an hour of reaction under the ice-bath condition, the reaction is carried out at normal temperature for about 1 hour, water is added for quenching reaction, reaction liquid is extracted by dichloromethane, organic phases are combined and concentrated to obtain a white solid crude product, and the white solid crude product is directly subjected to the next reaction without purification. Adding 1.2eq of the product into dry dichloromethane, then adding 1eq of a raw material A, finally adding 2eq of DIPEA, stirring for about 2 hours, detecting the reaction by thin-layer chromatography, finding complete reaction, adding water to quench the reaction, extracting the reaction solution by dichloromethane, combining concentrated organic phases, directly putting the mixture into the next reaction without purification, adding an ethyl acetate hydrochloride solution into the mixture, monitoring the reaction by thin-layer chromatography until the raw material disappears, spin-drying the reaction solution, extracting by dichloromethane, washing by saturated sodium bicarbonate, combining the organic phases, and carrying out column chromatography to obtain a product.
Preparation of compound I: dissolving NHS 1eq in dry dichloromethane, adding Boc protected amino acid 1.2eq, adding EDCI 1.8eq under ice bath condition, reacting for half an hour under ice bath condition, removing ice bath, reacting at normal temperature for about 1 hour, adding water to quench the reaction, extracting the reaction solution with dichloromethane, combining and concentrating organic phases to obtain a white solid crude product, and directly carrying out the next reaction without purification. Adding 1.2eq of the product into dry dichloromethane, then adding 1eq of raw material A, finally adding 2eq of DIPEA, stirring for about 2 hours, detecting the reaction by thin-layer chromatography, finding complete reaction, adding water to quench the reaction, extracting the reaction solution by dichloromethane, combining concentrated organic phases, directly putting the mixture into the next reaction without purification, dissolving the mixture in acetone, adding 1.5eq of cesium carbonate, adding 1.2eq of iodomethane, monitoring the reaction by thin-layer chromatography until the raw material disappears, spin-drying the reaction solution, extracting by dichloromethane, combining concentrated organic phases, directly carrying out the next reaction without purification, adding an ethyl acetate hydrochloride solution into the mixture, monitoring the reaction by thin-layer chromatography until the raw material disappears, spin-drying the reaction solution, extracting by dichloromethane, washing by saturated sodium bicarbonate, combining the organic phases, and carrying out column chromatography to obtain the product.
Referring to the above process, the present invention prepares the following organic arsenic compounds:
Figure BDA0001837686510000111
Figure BDA0001837686510000121
example 1
A target object:
Figure BDA0001837686510000122
uniformly mixing 30mL of methanol and 24mL of concentrated hydrochloric acid, adding 13.2g of rocarsone into the mixture, finally adding 100mg of potassium iodide, introducing sulfur dioxide gas in the stirring process, reacting for about half an hour to stop the reaction, stirring under the ice bath condition, slowly adding concentrated ammonia water until the pH value is about 8, standing the reaction solution, demixing the reaction solution, pouring out the upper-layer liquid to obtain a viscous yellow solid at the lower layer, adding ethanol to dissolve the viscous substance, adding 2.6mL of ethanedithiol after clarification and transparency, generating a large amount of bright yellow solid precipitates in the dropwise adding process, refluxing for half an hour after the dropwise adding is finished, cooling, filtering a solid product, rinsing a filter cake with ethanol, combining filtrate and carrying out column chromatography to obtain 5.7g of the product. Dissolving the product in acetone, adding water the volume of which is half of that of the acetone, finally slowly adding sodium hydrosulfite the equivalent weight of which is 20 times of that of the acetone, reacting for half an hour, adding a large amount of water to quench the reaction, directly extracting the reaction solution by using ethyl acetate, and carrying out column chromatography to obtain the product.
The reaction is as follows:
Figure BDA0001837686510000131
yield: 27%;1H NMR(DMSO-d6，400MHz)δ：6.829(s，1H，Ar-H)，6.649(s，2H，Ar-H)，4.660(br，2H，NH2-H)，3.366-3.303(m，2H，-S-CH2- 2CH-S-)，3.248-3.185(m，2H，-S- 2CH-CH2-S-)；13C NMR(DMSO-d6，100MHz)δ：145.50，136.96，132.11，119.15，116.04，114.00，41.20；MS-ESI m/z：275.8[M+H]+.
example 2
A target object:
Figure BDA0001837686510000132
uniformly mixing 30mL of methanol and 24mL of concentrated hydrochloric acid, adding 10.9g of sulfanilic acid, finally adding 100mg of potassium iodide, introducing sulfur dioxide gas in the stirring process, stopping the reaction for about half an hour, directly filtering, adding filter residues into a flask, adding concentrated ammonia water to adjust the pH value to about 8, performing suction filtration again to obtain an off-white solid product, adding the off-white solid product into the round-bottom flask, adding a proper amount of ethanol and ethanedithiol, refluxing for half an hour, and performing column chromatography to obtain a white final product.
The reaction is as follows:
Figure BDA0001837686510000141
yield: 47%;1H NMR(CDCl3，400MHz)δ：7.441-7.408(d，2H，J＝8.4Hz，Ar-H)，6.679-6.646(d，2H，J＝8.4Hz，Ar-H)，3.792(s，2H，NH2-H)，3.380-3.310(m，2H，-S- 2CH-CH2-S-)，3.252-3.182(m，2H，-S-CH2- 2CH-S-)；13C NMR(CDCl3，100MHz)δ：147.54，132.06，131.21，114.84，41.55；MS-ESI m/z：260.2[M+H]+.
example 3
Figure BDA0001837686510000142
Just as in example 2, o-aminobenzenearsonic acid was used instead of p-aminobenzenearsonic acid. The detection data of the product obtained by the reaction are as follows: yield: 38 percent;1H NMR(CDCl3，400MHz)δ：7.603-7.587(d，1H，J＝6.4Hz，Ar-H)，7.185-7.147(t，1H，J＝8Hz，Ar-H)，6.856-6.821(t，1H，J＝7.6Hz，Ar-H)，6.697-6.677(d，1H，J＝8Hz，C12-H)，3.420-3.357(m，2H，-S-CH2- 2CH-S-)，3.222-3.148(m，2H，-S- 2CH-CH2-S-)；13C NMR(CDCl3，100MHz)δ：148.302，132.208，130.842，126.629，119.742，117.721，41.900；MS-ESI m/z：260.0[M+H]+.
example 4
Figure BDA0001837686510000151
Preparing m-nitrobenzene fluoroboric acid diazonium salt: 31.5mL of concentrated hydrochloric acid and 25mL of water were mixed uniformly, and then 17.25g of m-nitroaniline was added thereto and stirred uniformly. Placing in a low-temperature reactor at 0 ℃. After cooling was complete, sodium nitrite solution (8.65g sodium nitrite in 20mL water) was added dropwise to the ice bath solution, with potassium iodide starch indicating the end point. After the diazonium salt is made, a sodium fluoroborate solution (27.5g sodium fluoroborate dissolved in 55mL water) is added dropwise to the diazonium salt solution in a low temperature reactor at 0 ℃. The reaction solution is observed to be more and more turbid and thick, the reaction is lifted after 30 minutes of reaction, suction filtration is carried out until no liquid is left, the filter cake is washed twice by ice water until no liquid is left, the filter cake is washed twice by using glacial methanol until no liquid is left, and the filter cake is washed twice by using glacial ethyl ether until no liquid is left. And (5) drying for later use.
Preparing a sodium arsenite solution: mixing 8g of sodium hydroxide and 300mL of water, clarifying, adding 26g of sodium arsenite, stirring, clarifying the solution, adding 3g of cuprous chloride, and uniformly stirring to obtain the sodium arsenite solution.
Preparation of m-nitrobenzene arsenic acid: the previously prepared diazonium fluoroborate solid was stirred well in 150mL of water. This solution was added to the sodium arsenite solution within 1 hour. After the addition, the reaction was carried out for 1 hour. Adding 50mL of 10% sodium hydroxide solution, reacting for 1 hour, placing the reaction system in 60 ℃, reacting for 30 minutes, carrying out suction filtration while the reaction is hot, washing a filter cake with water, and adjusting the pH of the filtrate with concentrated hydrochloric acid until the color of the litmus blue test paper changes. The solution was filtered with suction, the filter cake was washed with a small amount of water, activated carbon was added to the filtrate, and the mixture was concentrated to 175mL by heating. The black liquid was filtered while hot to give an almost colorless filtrate, the pH of the filtrate was adjusted with concentrated hydrochloric acid until the color of Congo red paper became just changed, and the liquid was left in a refrigerator overnight. The next morning, a large number of white flaky crystals were found to precipitate at the bottom of the flask. And (4) carrying out suction filtration to obtain a product. The product was washed with ice water and left to dry for further use. The filtrate was again concentrated to 75mL, placed in the refrigerator again overnight and filtered to give the product. And (5) drying for later use.
Preparing m-nitrobenzene arsenic oxygen: mixing m-nitrobenzene arsenic acid, methanol, concentrated hydrochloric acid and potassium iodide uniformly, and introducing SO into the solution2The solution was observed to change from white turbidity to light yellow slightly turbid, and the reaction was terminated when no iodine was formed. After the reaction, methanol in the solution is evaporated out under reduced pressure, water in the solution is sucked off, and the product is yellow opaque oil and is dried for later use.
Preparing m-nitroaniline arsenic five-membered disulfide: dissolving m-nitrobenzene arsenic oxide in ethanol, slowly dripping ethanedithiol, refluxing for about half an hour after dripping, concentrating under pressure, and performing column chromatography to obtain a yellow product.
Sixthly, synthesizing the final product: dissolving m-nitroaniline arsenic penta-disulfide ring in acetone, adding water with half volume of the acetone, stirring uniformly, adding sodium hydrosulfite, stirring, and reacting at 50 ℃ for half an hour. Extracting with ethyl acetate, concentrating, and performing column chromatography to obtain light yellow product.
The reaction is as follows:
Figure BDA0001837686510000161
yield: 12 percent;1H NMR(DMSO-d6，400MHz)δ：7.040-7.002(t，1H，J＝7.6Hz，Ar-H)，6.804(s，1H，Ar-H)，6.732-6.714(d，1H，J＝7.2Hz，Ar-H)，6.524-6.504(d，1H，J＝8Hz，Ar-H)，5.213(s，2H，NH2-H)，3.399-3.341(m，2H，-S-CH2- 2CH-S-)，3.206-3.123(m，2H，-S- 2CH-CH2-S-)；13C NMR(DMSO-d6，100MHz)δ：148.717，143.468，128.791，117.536，115.380，114.675，41.384；MS-ESI m/z：259.8[M+H]+.
example 5
Figure BDA0001837686510000162
Dissolving 1.5eq of Boc protected glycine in dry dichloromethane, stirring uniformly, adding EDCI 3eq under ice bath condition, adding HOBT 2eq after stirring for about 5 minutes, adding raw materials (the compound in example 2) 1eq after stirring for about 5 minutes, stirring for half an hour under ice bath condition, removing the ice bath, and reacting at room temperature overnight. The next day the reaction was quenched by addition of water, extracted with dichloromethane, and the reaction was washed with water. And combining the concentrated organic phases, directly carrying out the next reaction without purification, adding an ethyl acetate hydrochloride solution into the concentrated organic phases, monitoring the reaction by using thin-layer chromatography until the raw materials disappear, spin-drying the reaction liquid, extracting by using dichloromethane, washing by using saturated sodium bicarbonate, combining the organic phases, and carrying out column chromatography to obtain the product.
The reaction is as follows:
Figure BDA0001837686510000171
the detection data of the product obtained by the reaction are as follows: yield: 14 percent;1H NMR(DMSO-d6，400MHz)δ：7.666-7.644(d，2H，J＝8.8Hz，Ar-H)，7.577-7.556(d，2H，J＝8.4Hz，Ar-H)，3.391-3.340(m，2H，-S-CH2- 2CH-S-)，3.263(s，2H，-CO 2CH-NH2)，3.198-3.126(m，8H，-S- 2CH-CH2-S-)；13C NMR(DMSO-d6，100MHz)δ：172.267，139.697，137.101，131.323，118.736，45.522，41.366；MS-ESI m/z：317.7[M+H]+.
example 6
Figure BDA0001837686510000172
The same as in example 5, only the compound of example 3 was used as the corresponding starting material in place of the compound of example 2. The detection data of the product obtained by the reaction are as follows: yield: 15 percent;1H NMR(DMSO-d6，400MHz)δ：7.795-7.777(d，1H，J＝7.2Hz，Ar-H)，7.354-7.321(m，2H，Ar-H)，7.224-7.189(m，1H，Ar-H)，4.769(br，2H，NH2-H)，3.339-3.277(m，4H，-CO 2CHNH2，-S-CH2- 2CH-S-)，3.134(m，2H，-S- 2CH-CH2-S-)；13C NMR(DMSO-d6，100MHz)δ：172.559，138.942，136.398，131.812，129.680，125.014，123.855，45.099，41.231；MS-ESI m/z：316.7[M+H]+.
example 7
Figure BDA0001837686510000181
Dissolving NHS 1eq in dry dichloromethane, adding Boc protected glycine 1.2eq, adding EDCI 1.8eq under ice bath condition, reacting for half an hour under ice bath condition, removing ice bath, reacting at normal temperature for about 1 hour, adding water to quench the reaction, extracting the reaction solution with dichloromethane, combining and concentrating organic phases to obtain a white solid crude product, and directly carrying out the next reaction without purification. Adding 1.2eq of the product into dry dichloromethane, then adding 1eq of the final compound in example 1, finally adding 2eq of DIPEA, stirring for about 2 hours, detecting the reaction by thin-layer chromatography, finding the reaction is complete, adding water to quench the reaction, extracting the reaction solution by dichloromethane, combining concentrated organic phases, directly putting the mixture into the next reaction without purification, adding an ethyl acetate hydrochloride solution into the mixture, monitoring the reaction by thin-layer chromatography until the raw materials disappear, spin-drying the reaction solution, extracting by dichloromethane, washing by saturated sodium bicarbonate, combining the organic phases, and carrying out column chromatography to obtain the product.
The reaction is as follows:
Figure BDA0001837686510000182
yield: 8 percent;1H NMR(DMSO-d6，400MHz)δ：8.495(s，1H，Ar-H)，7.168-7.148(d，1H，J＝8Hz，Ar-H)，6.900-6.880(d，1H，J＝8Hz，Ar-H)，3.390-3.335(m，2H，-S-CH2- 2CH-S-)，3.260(s，2H，-CO 2CHNH2)，3.233-3.166(m，2H，-S-CH2- 2CH-S-)；13C NMR(DMSO-d6，100MHz)δ：171.242，148.120，131.978，126.725，126.241，121.346，114.584，45.036，41.321；MS-ESI m/z：746.6[M+Na]+.
example 8
Figure BDA0001837686510000191
Dissolving NHS 1eq in dry dichloromethane, adding Boc protected glycine 1.2eq, adding EDCI 1.8eq under ice bath condition, reacting for half an hour under ice bath condition, removing ice bath, reacting at normal temperature for about 1 hour, adding water to quench the reaction, extracting the reaction solution with dichloromethane, combining and concentrating organic phases to obtain a white solid crude product, and directly carrying out the next reaction without purification. Adding 1.2eq of the product into dry dichloromethane, then adding 1eq of the final compound in example 1, finally adding 2eq of DIPEA, stirring for about 2 hours, detecting reaction by thin-layer chromatography, finding complete reaction, adding water to quench the reaction, extracting the reaction solution by dichloromethane, combining concentrated organic phases, directly putting the mixture into the next reaction without purification, dissolving the mixture in acetone, adding 1.5eq of cesium carbonate, then adding 1.2eq of iodomethane, monitoring the reaction by thin-layer chromatography until the raw materials disappear, spin-drying the reaction solution, extracting by dichloromethane, combining the concentrated organic phases, directly carrying out the next reaction without purification, adding ethyl acetate hydrochloride solution into the mixture, monitoring the reaction by thin-layer chromatography until the raw materials disappear, spin-drying the reaction solution, extracting by dichloromethane, washing by saturated sodium bicarbonate, combining the organic phases, and carrying out column chromatography to obtain the product.
The reaction is as follows:
Figure BDA0001837686510000192
the detection data of the product obtained by the reaction are as follows: yield: 14 percent;1H NMR(DMSO-d6，400MHz)δ：8.598(s，1H，Ar-H)，7.310-7.295(d，1H，J＝6Hz，Ar-H)，7.089-7.068(d，1H，J＝8.4Hz，Ar-H)，3.865(s，3H，-O 3CH)，3.398-3.361(m，2H，-S-CH2- 2CH-S-)，3.266(s，2H，-CO 2CHNH2)，3.223-3.162(m，2H，-S- 2CH-CH2-S-)；13C NMR(DMSO-d6，100MHz)δ：171.550，149.007，134.335，127.335，126.074，120.680，110.639，55.980，45.161，41.375；MS-ESI m/z：347.1[M+H]+.
the organic arsenic compounds 1, 3, 5, 7, 9, 11-13, 15-19, 21-25, 27-30, and 32 were prepared as described above, except that the corresponding ethanedithiol and/or Boc-protected glycine was replaced with a propanedithiol and/or Boc-protected amino acid.
Test method and results of thioredoxin reductase inhibitory activity and antitumor activity of the organic arsenic compound
The cytotoxicity test of the invention adopts MTT method. Drugs with different concentrations are added into a 96-well plate, cells are inoculated, 50 mu L of culture medium containing 1 ten thousand cells is added into each well, and the cells are allowed to adhere to the wall for 24 hours. After the drug was applied for the prescribed time, the wells were aspirated of the medium, the cells were washed twice with PBS, and then 100. mu.L of the medium was added to the wells, followed by addition of 10. mu.L of MTT (5mg/mL) for further culture. After 4h, 100 μ L of the triple lysis solution was added to the wells and incubated overnight, and then the absorbance (λ 570nm) in the wells was measured. The final Cell viability was calculated as Cell viability% (A)drug-Ablank)/(ADMSO-Ablank)。
The enzyme inhibitory activity of the present invention employs an insulin end-point method. The cells were collected and the protein was extracted, the cells were seeded in 60mm culture dishes, 4mL of medium containing 100 ten thousand cells was added to each dish, and after 24h, the medium containing the drug was added to the dish. After 24h of drug action, cells were collected. The collected cells were lysed with RIPA lysate, the protein was quantified with coomassie brilliant blue after collection, and finally all protein concentrations were adjusted to be identical. The corresponding reagent was added to the well, the main mixture was composed of 100mM Tris-HCl (pH 7.6), 0.3mM insulin, 660. mu.M NADPH, and after 30min reaction at 37 ℃, 200. mu.L guanidine hydrochloride (6M) containing 1mM DTNB was added to the system, and after 5min absorbance at A412 was measured, and finally the enzyme activity was calculated.
TABLE 1 results of the toxic Activity of organic arsenic Compounds on HL-60 cells
Figure BDA0001837686510000211
TABLE 2 IC50 values for the cytotoxic activity of organoarsenic compounds against HL-60
Figure BDA0001837686510000212
TABLE 3 IC50 values for inhibitory Activity of organic arsenic Compounds on HL-60 intracellular TrxR
Figure BDA0001837686510000213
The above results show that the organic arsenic compound of the present invention has a good cytotoxic effect on tumor cell HL-60 cells, and can effectively inhibit the activity of TrxR in the cells, which indicates that the organic arsenic compound can be used for preparing thioredoxin reductase inhibitors or antitumor drugs taking thioredoxin reductase as a target, wherein the pharmaceutical activity of the organic arsenic compound 4, 5, 11-13, 17-19, 23-25, 29-30 is relatively good, and the organic arsenic compound 3 (i.e., organic arsenic compound 3) is relatively good (i.e., thioredoxin reductase is used as a target)
Figure BDA0001837686510000221
) The pharmaceutical activity of (a) is optimal.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.

Claims (4)

1. An organic arsenic compound characterized by: the organic arsenic compound is specifically:
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、
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、
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、
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、
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、
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、
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、
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、
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、
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。
2. use of the organoarsenic compound of claim 1, wherein: the application of the organic arsenic compound in preparing thioredoxin reductase inhibitors.
3. Use of the organoarsenic compound of claim 1, wherein: the organic arsenic compound is applied to the preparation of antitumor drugs.
4. Use according to claim 3, characterized in that: the anti-tumor drug is an anti-leukemia drug.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102807588A (en) * 2011-06-02 2012-12-05 华东理工大学 Compound and method for in-situ detecting o-sulfhydryl protein in organism
CN105175470A (en) * 2015-07-24 2015-12-23 湖北工程学院 Arsenic sugar compound with anti-tumor activity and preparation method therefor and application thereof
CN107814796A (en) * 2017-10-16 2018-03-20 湖南大学 A kind of environment sensitive dyestuff based on benzofuraxan and its preparation method and application

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102807588A (en) * 2011-06-02 2012-12-05 华东理工大学 Compound and method for in-situ detecting o-sulfhydryl protein in organism
CN105175470A (en) * 2015-07-24 2015-12-23 湖北工程学院 Arsenic sugar compound with anti-tumor activity and preparation method therefor and application thereof
CN107814796A (en) * 2017-10-16 2018-03-20 湖南大学 A kind of environment sensitive dyestuff based on benzofuraxan and its preparation method and application

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Dithiaarsanes Induce Oxidative Stress-Mediated Apoptosis in HL-60 Cells by Selectively Targeting Thioredoxin Reductase;Yaping Liu 等;《J. Med. Chem.》;20140527;第57卷;第5203-5211页 *
Organic arsenicals target thioredoxin reductase followed by oxidative stress and mitochondrial dysfunction resulting in apoptosis;Xiao-Yang Fan 等;《European Journal of Medicinal Chemistry》;20170506;第143卷;第1090-1102页 *
Sensitive method for the determination of roxarsone using solid-phase microextraction with multi-detector gas chromatography;Aaron R. Roerdink 等;《J. Chromatogr. A》;20041231;第1057卷;第177-183页 *

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