Six-membered cyclic organic arsenic compound and preparation method thereof, biotin-modified nano material and antitumor drug

Abstract

The invention discloses a six-membered cyclic organic arsenic compound and a preparation method thereof, a biotin-modified nano material and an antitumor drug, and belongs to the technical field of medicinal chemistry. The structural formula of the six-membered cyclic organic arsenic compound is as follows: # imgabs0. The six-membered cyclic organic arsenic compound synthesized by the invention has a symmetrical and regular geometric structure, and is beneficial to keeping the stability of the structure; the structure of the compound is small, exquisite and simple, the steric hindrance with a specific binding site is small, targeted binding with a protein target is facilitated, and the toxicity is lower while the biological activity of arsenic is kept. The biotin-modified nano material prepared from the organic arsenic compound can improve the enrichment degree of tumor tissues, trigger intracellular biochemical reaction, improve the antitumor activity in tumor-bearing mice and reduce toxic and side effects.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemistry, and particularly relates to a six-membered cyclic organic arsenic compound, a preparation method thereof, a biotin-modified nanomaterial, and an anti-tumor drug. Background Art

[0002] Arsenic is a semi-metallic element with both metallic and non-metallic properties. Arsenic is widely distributed in nature and mainly exists in three inorganic forms, namely realgar (As4S4), orpiment (As2S3), and arsenic trioxide (As2O3). As early as the Warring States period, inorganic arsenic drugs were used for the treatment of diseases; and there were clear and detailed records in the "Compendium of Materia Medica" in the Ming Dynasty. Since modern times, arsenic trioxide (ATO) has shown significant effects in the treatment of acute promyelocytic leukemia (APL), but its high toxicity and side effects have greatly limited its application in clinical solid tumors.

[0003] Compared with inorganic arsenic drugs, the toxicity of organic arsenic compounds is significantly reduced. The first modern chemotherapy drug, Salvarsan, can penetrate into specific parts of the human body to kill the spirochetes causing syphilis. Before the emergence of penicillin, it had been used as a specific drug for the treatment of syphilis. However, its structure is not stable, and it has high toxicity to the liver and kidneys and many side effects. Therefore, it is crucial to develop a new type of anti-cancer organic arsenic compound with a simple structure, high targeting property, and good activity. Summary of the Invention

[0004] Aiming at the deficiencies of the prior art, the present invention provides a six-membered cyclic organic arsenic compound, a preparation method thereof, a biotin-modified nanomaterial, and an anti-tumor drug to solve the above problems.

[0005] The technical solution of the present invention is as follows:

[0006] In the first aspect of the present invention, a six-membered cyclic organic arsenic compound is provided, and the structural formula of the six-membered cyclic organic arsenic compound is as follows:

[0007]

[0008] In the second aspect of the present invention, a preparation method of the six-membered cyclic organic arsenic compound described in the first aspect is provided, including the following steps:

[0009] Mix phenylarsonic acid with a reducing agent, add a solvent and react to obtain product 1; recrystallize product 1 and freeze-dry it to obtain the six-membered cyclic organic arsenic compound.

[0010] Preferably, the reducing agent is at least one of hypophosphorous acid and phosphorous acid; and / or,

[0011] The mass-volume ratio of the phenylarsonic acid to the reducing agent is 10 g: 8 - 13 mL;

[0012] The solvent includes at least one of ethanol, methanol, and isopropanol; and / or,

[0013] The ethanol is anhydrous ethanol; and / or,

[0014] The volume ratio of the solvent to the reducing agent is 1:1 to 4:1.

[0015] Preferably, the reaction is carried out under nitrogen protection, with stirring at 70-80 °C for 3-5 h; and / or,

[0016] The solution for recrystallization is a mixed solution of benzene and chlorobenzene; the volume ratio of benzene to chlorobenzene is 3-5:1; and / or,

[0017] The solution for recrystallization is a mixed solution of chloroform and n-pentane; the volume ratio of n-pentane to chlorobenzene is 3-5:1;

[0018] The conditions for recrystallization are 2-8 °C, with standing for 12-24 h.

[0019] Preferably, the temperature for freeze-drying is -40 to -80 °C, and the time is 24-96 h.

[0020] The third aspect of the present invention provides a biotin-modified nanomaterial, which comprises the six-membered cyclic organoarsenic compound described in the first aspect above, or the six-membered cyclic organoarsenic compound prepared by the preparation method described in the second aspect above.

[0021] Preferably, the nanomaterial is obtained by dissolving the six-membered cyclic organoarsenic compound in a solvent to obtain a six-membered cyclic organoarsenic compound solution, then adding a phospholipid-polyethylene glycol-biotin solution, followed by ultrasonic dispersion and rotary evaporation.

[0022] Preferably, the solvent I includes at least one of n-hexane, dichloromethane, chloroform, methanol, ethanol, isopropanol, and dimethyl sulfoxide; and / or, the concentration of the six-membered cyclic organoarsenic compound solution is 1-1.5 mg / mL; and / or,

[0023] The phospholipid-polyethylene glycol-biotin solution is obtained by mixing phospholipid-polyethylene glycol-biotin with a solvent II; and / or,

[0024] The solvent II includes at least one of water, phosphate buffer solution, and physiological saline; and / or,

[0025] The mass ratio of the six-membered cyclic organoarsenic to the phospholipid-polyethylene glycol-biotin is 1-2:1-2; and / or,

[0026] The volume ratio of the solvent I to the solvent II is 1:1 to 2; and / or,

[0027] The phospholipid polyethylene glycol biotin is distearoyl phosphatidylethanolamine - polyethylene glycol 2000 - biotin.

[0028] Preferably, the power of the ultrasound is 100 - 400 W and the time is 60 - 90 min; and / or,

[0029] The temperature of the rotary evaporation is ≤ 40°C.

[0030] The fourth aspect of the present invention provides an anti - tumor drug, comprising the six - membered cyclic organoarsenic compound described in the first aspect above, or the six - membered cyclic organoarsenic compound described in the second aspect above, or the biotin described in the third aspect above.

[0031] The beneficial technical effects of the present invention are as follows:

[0032] The six - membered cyclic organoarsenic compound synthesized by the present invention has a symmetric and regular geometric structure, which is beneficial to maintaining the structural stability; and the structure of the compound is small and simple, with a small steric hindrance to specific binding sites, which is beneficial to the targeted binding with protein targets; compared with inorganic arsenic, the organoarsenic compound synthesized by the present invention has lower toxicity while maintaining the biological activity of arsenic.

[0033] The synthesis process, purification and separation of the six - membered cyclic organoarsenic compound of the present invention are simple. Specifically, the reaction of the present invention is a one - step synthesis reaction, with few types of reaction raw materials, easy to purchase and low in price, and the production equipment, process conditions and steps are simple, suitable for industrial production.

[0034] At the same time, the present invention also uses this organoarsenic compound to prepare a biotin - modified nanomaterial, which has a high specific surface area and surface biotin modification, is beneficial to improving the enrichment degree in tumor tissues, triggering intracellular biochemical reactions, enhancing the anti - tumor activity in tumor - bearing mice and reducing the toxic and side effects.

[0035] The six - membered cyclic organoarsenic compound (AsPh)6 synthesized by the present invention and the biotin - modified nanomaterial (AsPh)6@DSPE - PEG 2000 - Biotin ((AsPh)6@DPB) has strong practicability and obvious anti - tumor activity. Specifically:

[0036] 1) The six - membered cyclic organoarsenic compound (AsPh)6 and the biotin - modified nanomaterial (AsPh)6@DSPE - PEG 2000 - Biotin ((AsPh)6@DPB) has obvious cytotoxic effects on a variety of tumor cell lines, while having weak toxicity to normal cells.

[0037] 2) The six - membered cyclic organoarsenic compound (AsPh)6 and the biotin - modified nanomaterial (AsPh)6@DSPE - PEG 2000-Biotin((AsPh)6@DPB) can target zinc transporters in pancreatic cancer cells, leading to the disruption of zinc homeostasis, thereby inducing the occurrence of tumor cell apoptosis and exerting an anti-tumor effect. Description of the Drawings

[0038] Figure 1 It is a schematic chemical structure diagram of the hexacyclic organoarsenic compound (AsPh)6, which is the product of the present invention.

[0039] Figure 2 It is a mass spectrometry spectrum of the hexacyclic organoarsenic compound (AsPh)6, which is the product of the present invention.

[0040] Figure 3 It is a transmission electron microscope photograph of the biotinylated nanomaterial (AsPh)6@DSPE-PEG 2000 -Biotin((AsPh)6@DPB) of the present invention.

[0041] Figure 4 It is a scanning electron microscope photograph of the biotinylated nanomaterial (AsPh)6@DSPE-PEG 2000 -Biotin((AsPh)6@DPB) of the present invention.

[0042] Figure 5 It is an elemental analysis mapping photograph of the biotinylated nanomaterial (AsPh)6@DSPE-PEG 2000 -Biotin((AsPh)6@DPB) of the present invention.

[0043] Figure 6 It is a dynamic light scattering particle size analysis diagram of the biotinylated nanomaterial (AsPh)6@DSPE-PEG 2000 -Biotin((AsPh)6@DPB) of the present invention.

[0044] Figure 7 It is a comparison diagram of cell live / dead staining of the present invention.

[0045] Figure 8 It is an uptake diagram of the products (AsPh)6 and (AsPh)6@DSPE-PEG 2000 -Biotin of the present invention in human in situ pancreatic adenocarcinoma cell line BxPC-3 in vitro.

[0046] Figure 9 It is an organelle distribution diagram of the products (AsPh)6 and (AsPh)6@DSPE-PEG 2000 -Biotin of the present invention in human in situ pancreatic adenocarcinoma cell line BxPC-3 in vitro.

[0047] Figure 10The products of the present invention, (AsPh)6 and (AsPh)6@DSPE-PEG 2000 -Biotin. Comparison chart of the changes in the zinc content in the cells and cell organelles of human in situ pancreatic adenocarcinoma cell line BxPC-3 in vitro.

[0048] Figure 11 The products of the present invention, (AsPh)6 and (AsPh)6@DSPE-PEG 2000 -Biotin. Comparison chart of the effects on the expression of a series of zinc-related proteins in human in situ pancreatic adenocarcinoma cell line BxPC-3 in vitro.

[0049] Figure 12 The products of the present invention, (AsPh)6 and (AsPh)6@DSPE-PEG 2000 -Biotin and the line chart of the tumor volume changes and the comparison chart of the tumor mass of other control experimental groups.

[0050] Figure 13 The products of the present invention, (AsPh)6 and (AsPh)6@DSPE-PEG 2000 -Biotin. Comparison of the enrichment in tumor tissues in vivo. Detailed implementation manners

[0051] The present invention will be specifically described below in conjunction with the embodiments.

[0052] Based on the problems of existing organoarsenic compounds and their re-preparation of anti-cancer drugs, the present invention provides a six-membered cyclic organoarsenic compound, its preparation method, a biotin-modified nanomaterial and an anti-tumor drug, in order to solve the above technical problems.

[0053] The first aspect of the present invention provides a six-membered cyclic organoarsenic compound, and the structural formula of the six-membered cyclic organoarsenic compound (AsPh)6 is as follows:

[0054]

[0055] It can be understood that the six-membered cyclic organoarsenic compound (AsPh)6 of the present invention has a symmetric and regular geometric structure, is small in volume, has a small steric hindrance with specific binding sites, is conducive to the targeted binding with protein targets, has good anti-tumor activity, and realizes small molecule targeted tumor therapy. Compared with inorganic arsenic, the organoarsenic compound synthesized in the present invention has lower toxicity while maintaining the biological activity of arsenic. Through in vitro cytotoxicity tests on different tumor cell lines, the results show that the organoarsenic compound of the present invention induces apoptosis of pancreatic cancer cell lines by disrupting the zinc ion homeostasis, indicating that the six-membered cyclic organoarsenic compound (AsPh)6 has good anti-tumor biological activity.

[0056] The second aspect of the present invention provides a method for preparing the six-membered cyclic organoarsenic compound described in the first aspect above, comprising the following steps:

[0057] Mix phenylarsonic acid with a reducing agent, add a solvent and react to obtain product 1; recrystallize product 1 and freeze-dry to obtain the six-membered cyclic organoarsenic compound.

[0058] In some embodiments, the method for preparing product 1 comprises: adding phenylarsonic acid powder to a reaction tube, then adding hypophosphorous acid and ethanol, protecting with nitrogen, heating and reacting, and cooling to room temperature to obtain product 1.

[0059] In some embodiments, the six-membered cyclic organoarsenic compound (AsPh)6 is a pale yellow solid.

[0060] In some embodiments, the reducing agent comprises at least one of hypophosphorous acid and phosphorous acid.

[0061] It can be understood that in the present invention, phenylarsonic acid is reduced by using a reducing agent, and then the six-membered cyclic organoarsenic is obtained by recrystallization, and the preparation method is simple.

[0062] In some embodiments, the mass-volume ratio of the phenylarsonic acid to the reducing agent is 10 g: 8-13 mL.

[0063] In some embodiments, the solvent comprises at least one of methanol, ethanol, and isopropanol.

[0064] In some embodiments, the ethanol is anhydrous ethanol.

[0065] In some embodiments, the volume ratio of the solvent to the reducing agent is 1:1-4:1.

[0066] In some embodiments, the reaction is carried out under nitrogen protection, stirred at 70-80 °C for 3-5 h.

[0067] In some embodiments, the recrystallization solution is a mixed solution of benzene and chlorobenzene.

[0068] In some embodiments, the volume ratio of the benzene to the chlorobenzene is 3-5:1.

[0069] In some embodiments, the recrystallization solution is a mixed solution of chloroform and n-pentane; the volume ratio of the n-pentane to the chlorobenzene is 3-5:1.

[0070] In some embodiments, the recrystallization conditions are 2-8 °C, standing for 12-24 h.

[0071] In some embodiments, the temperature of the freeze-drying is -40 to -80 °C, and the time is 24-96 h.

[0072] The synthesis process, purification, and separation of the six-membered cyclic organoarsenic compound of the present invention are simple. Specifically, the reaction of the present invention is a one-step synthesis reaction. The types of reaction raw materials are few, easy to purchase, and inexpensive. The production equipment, process conditions, and steps are simple, making it suitable for industrial production.

[0073] The third aspect of the present invention provides a biotin-modified nanomaterial, which comprises the six-membered cyclic organoarsenic compound described in the first aspect above, or the six-membered cyclic organoarsenic compound prepared by the preparation method described in the second aspect above.

[0074] It can be understood that the nanomaterial of the present invention has a high specific surface area and surface biotin modification, which is beneficial to improving the enrichment degree in tumor tissues, triggering intracellular biochemical reactions, enhancing the anti-tumor activity in tumor-bearing mice, and reducing the toxic and side effects.

[0075] The six-membered cyclic organoarsenic compound (AsPh)6 and the biotin-modified nanomaterial (AsPh)6@DSPE-PEG 2000 -Biotin ((AsPh)6@DPB) synthesized in the present invention has strong practicability and obvious anti-tumor activity. Specifically: 1) The six-membered cyclic organoarsenic compound (AsPh)6 and the biotin-modified nanomaterial (AsPh)6@DSPE-PEG 2000 -Biotin ((AsPh)6@DPB) has obvious cytotoxic effects on a variety of tumor cell lines, but weak toxicity to normal cells. 2) The six-membered cyclic organoarsenic compound (AsPh)6 and the biotin-modified nanomaterial (AsPh)6@DSPE-PEG 2000 -Biotin ((AsPh)6@DPB) can target the zinc transporter in pancreatic cancer cells, leading to the disruption of zinc homeostasis, thereby inducing the apoptosis of tumor cells and exerting an anti-tumor effect.

[0076] In some embodiments, the nanomaterial is obtained by dissolving the six-membered cyclic organoarsenic compound (AsPh)6 in a solvent to obtain a six-membered cyclic organoarsenic compound solution, then adding a phospholipid-polyethylene glycol-biotin solution, followed by ultrasonic dispersion and rotary evaporation.

[0077] In some embodiments, the solvent I includes at least one of n-hexane, dichloromethane, chloroform, methanol, ethanol, isopropanol, and dimethyl sulfoxide.

[0078] In some embodiments, the concentration of the six-membered cyclic organoarsenic compound solution is 1-1.5 mg / mL.

[0079] In some embodiments, the phospholipid-polyethylene glycol-biotin solution is obtained by mixing phospholipid-polyethylene glycol-biotin with a solvent II.

[0080] In some embodiments, the solvent II includes at least one of water, phosphate buffer solution, and physiological saline.

[0081] In some embodiments, the mass ratio of the six-membered cyclic organoarsenic to the phospholipid polyethylene glycol biotin is 1-2:1-2.

[0082] In some embodiments, the volume ratio of the solvent I to the solvent II is 1:1-2.

[0083] In some embodiments, the phospholipid polyethylene glycol biotin is distearoyl phosphatidylethanolamine-polyethylene glycol 2000-biotin.

[0084] In some embodiments, the power of the ultrasound is 100-400 W, and the time is 60-90 min.

[0085] In some embodiments, the temperature of the rotary evaporation ≤ 40 °C.

[0086] In some embodiments, the rotary evaporation can remove the excess solvent. The selection step includes: in some embodiments, the emulsion after ultrasound is removed of the solvent by a rotary evaporator under reduced pressure and resuspended as an aqueous solution.

[0087] Preferably, the nanomaterial is a six-membered cyclic organoarsenic compound modified with distearoyl phosphatidylethanolamine-polyethylene glycol 2000-biotin (AsPh)6@DSPE-PEG 2000 -Biotin ((AsPh)6@DPB).

[0088] In the present invention, the average morphological particle size and the average hydrodynamic particle size of the nanomaterial modified with the biotin polymer DSPE-PEG 2000 -Biotin are 146.2 nm and 199.7 nm, respectively.

[0089] In the fourth aspect of the present invention, there is provided an anti-tumor drug, comprising the six-membered cyclic organoarsenic compound described in the first aspect above, or the six-membered cyclic organoarsenic compound described in the second aspect above, or the biotin described in the third aspect above. That is to say, the present invention provides the use of the six-membered cyclic organoarsenic compound, or the above-mentioned biotin in the preparation of anti-tumor drugs. The six-membered cyclic organoarsenic compound (AsPh)6 and the biotin-modified nanomaterial (AsPh)6@DSPE-PEG of the present invention 2000-Biotin ((AsPh)6@DPB) can effectively target tumor tissues, and by affecting the expression of zinc transporters in cells, hinder the cell's uptake of exogenous zinc ions, leading to the destruction of the original zinc homeostasis in cells, thereby inducing the occurrence of tumor cell apoptosis and effectively inhibiting the growth of tumors in tumor-bearing mice. It can be understood that the present invention modifies (AsPh)6 with biotin, and the biotin on the surface of the formed nanoparticles can specifically bind to the biotin receptors overexpressed on the surface of tumor cells, thereby having tumor targeting, and is expected to increase the enrichment of drugs in tumor tissues, thereby reducing drug accumulation in various organs and reducing its side effects in the body.

[0090] It is understood that, in the present invention, unless otherwise specified, the reagents used in the examples can be easily obtained from commercial companies or homemade.

[0091] The phenylarsenic acid used in the present invention, also known as phenylarsonic acid, was purchased from Shanghai Titan Technology Co., Ltd., item number 92045A; the hypophosphorous acid used was purchased from Shanghai Myrel Biochemical Technology Co., Ltd., item number M22198-250G.

[0092] The present invention is described in detail below in conjunction with the accompanying drawings and embodiments. The technical solution of the present invention is not limited to the specific implementations listed below, but also includes any combination of the specific implementations.

[0093] Example 1

[0094] A six-membered cyclic organic arsenic compound (AsPh)6, the synthesis method of which comprises the following steps:

[0095] (1) 10 g of phenylarsenic acid powder and 13 mL of hypophosphorous acid were loaded into a reaction tube, 15 mL of anhydrous ethanol was added, and the mixture was heated under reflux under nitrogen protection to obtain a product; wherein the reaction temperature was 75° C. and the reaction time was 4 hours.

[0096] (2) Add 10 mL of chlorobenzene to a 100 mL glass beaker, transfer the reaction product of step (1) to the chlorobenzene, stir until completely dissolved, slowly add 40 mL of benzene to the beaker, let stand at 4 ° C for 24 hours, freeze-dry the precipitated crystals at -80 ° C for 24 hours in a freeze dryer to completely remove the solvent (benzene and chlorobenzene), and obtain a light yellow solid, which is a six-membered cyclic organic arsenic compound (AsPh)6.

[0097] The structure and spectrum of the obtained six-membered cyclic organic arsenic compound (AsPh)6 are as follows: Figure 1 , Figure 2 shown.

[0098] 11H NMR (400 MHz, DMSO-d6) δ 7.83–7.73 (m, 6H), 7.66–7.59 (m, 12H), 7.41 (t, J = 6.2 Hz, 12H).

[0099] Example 2

[0100] A six-membered cyclic organoarsenic compound (AsPh)6, and its synthesis method includes the following steps:

[0101] (1) Load 10 g of phenylarsonic acid powder and 10 mL of hypophosphorous acid into a reaction tube, add 15 mL of absolute ethanol, and heat under reflux under nitrogen protection to obtain a product; wherein, the reaction temperature is 80 °C and the reaction time is 3 hours.

[0102] (2) Add 10 mL of chlorobenzene to a 100 mL glass beaker, transfer the reaction product of step (1) to the chlorobenzene, stir until completely dissolved, slowly add 40 mL of benzene to the beaker, let it stand at 4 °C for 20 hours, and freeze-dry the precipitated crystals at -80 °C for 48 hours using a freeze dryer to completely remove the solvents (benzene and chlorobenzene), and a pale yellow solid can be obtained, which is the six-membered cyclic organoarsenic compound (AsPh)6.

[0103] Example 3

[0104] A six-membered cyclic organoarsenic compound (AsPh)6, and its synthesis method includes the following steps:

[0105] (1) Load 10 g of phenylarsonic acid powder and 9 mL of hypophosphorous acid into a reaction tube, add 16 mL of absolute ethanol, and heat under reflux under nitrogen protection to obtain a product; wherein, the reaction temperature is 70 °C and the reaction time is 5 hours.

[0106] (2) Add 10 mL of chlorobenzene to a 100 mL glass beaker, transfer the reaction product of step (1) to the chlorobenzene, stir until completely dissolved, slowly add 40 mL of benzene to the beaker, let it stand at 4 °C for 24 hours, and freeze-dry the precipitated crystals at -80 °C for 72 hours using a freeze dryer to completely remove the solvents (benzene and chlorobenzene), and a pale yellow solid can be obtained, which is the six-membered cyclic organoarsenic compound (AsPh)6.

[0107] Example 4

[0108] A six-membered cyclic organoarsenic compound (AsPh)6, and its synthesis method includes the following steps:

[0109] (1) Load 10 g of phenylarsonic acid powder and 11 mL of hypophosphorous acid into a reaction tube, add 14 mL of absolute ethanol, and heat under reflux under nitrogen protection to obtain a product; wherein, the reaction temperature is 75 °C and the reaction time is 4 hours.

[0110] (2) Add 8 mL of chlorobenzene to a 100 mL glass beaker. Transfer the reaction product from step (1) to the chlorobenzene and stir until completely dissolved. Slowly add 45 mL of benzene to the beaker and let it stand at 4 °C for 12 hours. Freeze-dry the precipitated crystals in a freeze-dryer at -80 °C for 48 hours to completely remove the solvents (benzene and chlorobenzene), and a pale yellow solid, namely the six-membered cyclic organoarsenic compound (AsPh)6, can be obtained.

[0111] Example 5

[0112] A six-membered cyclic organoarsenic compound (AsPh)6 and its synthesis method, including the following steps:

[0113] (1) Load 10 g of phenylarsonic acid powder and 10 mL of hypophosphorous acid into a reaction tube, add 15 mL of absolute ethanol, and heat under reflux to obtain a product under nitrogen protection; among them, the reaction temperature is 80 °C and the reaction time is 3 hours.

[0114] (2) Add 10 mL of chlorobenzene to a 100 mL glass beaker. Transfer the reaction product from step (1) to the chlorobenzene and stir until completely dissolved. Slowly add 40 mL of benzene to the beaker and let it stand at 4 °C for 24 hours. Freeze-dry the precipitated crystals in a freeze-dryer at -80 °C for 48 hours to completely remove the solvents (benzene and chlorobenzene), and a pale yellow solid, namely the six-membered cyclic organoarsenic compound (AsPh)6, can be obtained.

[0115] By comparing Examples 1-5, it can be seen that 10 g of phenylarsonic acid powder can be reduced by 8-13 mL of hypophosphorous acid and react in a 10-20 mL absolute ethanol solution. This reaction needs to be carried out under nitrogen protection. After heating under reflux at 70-80 °C for 3-5 hours, the reaction is terminated. The reaction time should not be too long and the temperature should not be too high. The obtained crude reaction product has good solubility in chlorobenzene. Subsequently, an excessive amount of benzene is added as a poor solvent, and after standing, the organic solvents in the precipitated crystals are removed, and a pale yellow solid, namely the six-membered cyclic organoarsenic compound (AsPh)6, can be obtained.

[0116] Example 6

[0117] A biotin-modified nanomaterial (AsPh)6@DSPE-PEG 2000 - Biotin and its synthesis method, including the following steps:

[0118] (1) Load 10 mg of the six-membered cyclic organoarsenic compound (AsPh)6 powder synthesized according to Specific Example 1 and 10 mL of n-hexane into a 50 mL centrifuge tube in sequence, and assist dissolution by low-temperature ultrasonic treatment; among them, the ultrasonic power is 800 W and the ultrasonic time is 10 minutes.

[0119] (2) 10 mg of DSPE-PEG 2000- Biotin powder and 10 mL of water were successively loaded into a 50 mL centrifuge tube and stirred until completely dissolved.

[0120] (3) The solution obtained in step (1) was added to the solution obtained in step (2), ultrasonically dispersed, the solvent was removed by rotary evaporation, and it could be redispersed with 2 mL of water to obtain an off-white suspension; the ultrasonic power was 200 W and the ultrasonic time was 60 minutes; the temperature of the water bath during rotary evaporation should not exceed 40 °C.

[0121] Example 7

[0122] A biotin-modified nanomaterial (AsPh)6@DSPE-PEG 2000 - Biotin, and its synthesis method includes the following steps:

[0123] (1) 10 mg of the six-membered cyclic organoarsenic compound (AsPh)6 powder synthesized according to Specific Example 1 and 10 mL of n-hexane were successively loaded into a 50 mL centrifuge tube and ultrasonically assisted for dissolution at low temperature; the ultrasonic power was 800 W and the ultrasonic time was 10 minutes.

[0124] (2) 15 mg of DSPE-PEG 2000 - Biotin powder and 10 mL of water were successively loaded into a 50 mL centrifuge tube and stirred until completely dissolved.

[0125] (3) The solution obtained in step (1) was added to the solution obtained in step (2), ultrasonically dispersed, the solvent was removed by rotary evaporation, and it could be redispersed with 1 mL of water to obtain an off-white suspension; the ultrasonic power was 200 W and the ultrasonic time was 60 minutes; the temperature of the water bath during rotary evaporation should not exceed 40 °C.

[0126] Example 8

[0127] A biotin-modified nanomaterial (AsPh)6@DSPE-PEG 2000 - Biotin, and its synthesis method includes the following steps:

[0128] (1) 15 mg of the six-membered cyclic organoarsenic compound (AsPh)6 powder synthesized according to Specific Example 1 and 10 mL of n-hexane were successively loaded into a 50 mL centrifuge tube and ultrasonically assisted for dissolution at low temperature; the ultrasonic power was 800 W and the ultrasonic time was 10 minutes.

[0129] (2) 10 mg of DSPE-PEG 2000 - Biotin powder and 10 mL of water were successively loaded into a 50 mL centrifuge tube and stirred until completely dissolved.

[0130] (3) Add the solution obtained in step (1) to the solution obtained in step (2), disperse it by ultrasonic wave, remove the solvent by rotary evaporation, and resuspend it with 2 mL of water to obtain an off-white suspension; the ultrasonic power is 200 W and the ultrasonic time is 60 minutes; the temperature of the water bath during rotary evaporation shall not exceed 37 °C.

[0131] Example 9

[0132] A biotin-modified nanomaterial (AsPh)6@DSPE-PEG 2000 -Biotin, and its synthesis method includes the following steps:

[0133] (1) Load 10 mg of the six-membered cyclic organoarsenic compound (AsPh)6 powder synthesized according to Specific Example 1 and 10 mL of n-hexane into a 50 mL centrifuge tube in sequence, and assist dissolution by low-temperature ultrasonic wave; the ultrasonic power is 800 W and the ultrasonic time is 10 minutes.

[0134] (2) Load 10 mg of DSPE-PEG 2000 -Biotin powder and 10 mL of water into a 50 mL centrifuge tube in sequence, and ultrasonically dissolve until completely dissolved; during ultrasonic wave, the solution temperature shall not exceed 37 °C.

[0135] (3) Add the solution obtained in step (1) to the solution obtained in step (2), disperse it by ultrasonic wave, remove the solvent by rotary evaporation, and resuspend it with 2 mL of water to obtain an off-white suspension; the ultrasonic power is 200 W and the ultrasonic time is 60 minutes; the temperature of the water bath during rotary evaporation shall not exceed 40 °C.

[0136] Example 10

[0137] A biotin-modified nanomaterial (AsPh)6@DSPE-PEG 2000 -Biotin, and its synthesis method includes the following steps:

[0138] (1) Load 10 mg of the six-membered cyclic organoarsenic compound (AsPh)6 powder synthesized according to Specific Examples 1-5 and 10 mL of n-hexane into a 50 mL centrifuge tube in sequence, and assist dissolution by low-temperature ultrasonic wave; the ultrasonic power is 800 W and the ultrasonic time is 10 minutes.

[0139] (2) Load 10 mg of DSPE-PEG 2000 -Biotin powder and 10 mL of water into a 50 mL centrifuge tube in sequence, and vortex until completely dissolved.

[0140] (3) Add the solution obtained in step (1) to the solution obtained in step (2), disperse it by ultrasonic wave, and rotary evaporate to remove the solvent until 2 mL remains to obtain an off-white suspension; the ultrasonic power is 200 W and the ultrasonic time is 60 minutes; the temperature of the water bath during rotary evaporation shall not exceed 40 °C.

[0141] It can be seen from the comparison of Examples 6-10 that 10-15 mg of (AsPh)6 powder is dissolved in 10 mL of sufficient n-hexane and assisted by ultrasonic wave for dissolution; 10-15 mg of DSPE-PEG 2000 -Biotin is dissolved in 10 mL of sufficient ultrapure water and assisted by magnetic stirring for dissolution. Then the two components are mixed in equal volume, ultrasonicated and rotary evaporated. During the rotary evaporation process, the solutes dispersed in the two phases are further assembled into nanoparticles at the liquid surface. Among them, rotary evaporation is required in time after ultrasonic treatment, otherwise it will affect the particle size distribution of the nanomaterials.

[0142] Test example:

[0143] (1) Characterization and testing of biotin-modified nanomaterial (AsPh)6@DSPE-PEG 2000 -Biotin

[0144] (1-1) Particle size analysis of biotin-modified nanomaterial (AsPh)6@DSPE-PEG 2000 -Biotin

[0145] In the present invention, the particle size of the biotin-modified nanomaterial (AsPh)6@DSPE-PEG 2000 -Biotin prepared in Example 6 was tested by transmission electron microscopy (TEM) images and scanning electron microscopy (SEM) images respectively. The results are as Figures 3 - 4 shown. It can be seen from Figure 3 , 4 that the average particle size of the nanomaterial (AsPh)6@DSPE-PEG 2000 -Biotin synthesized and modified in Example 6 is 146.2 nm.

[0146] (1-2) Dynamic light scattering (DLS) particle size analysis of biotin-modified nanomaterial (AsPh)6@DSPE-PEG 2000 -Biotin

[0147] Figure 6 The dynamic light scattering (DLS) particle size analysis diagram of the biotin-modified nanomaterial (AsPh)6@DSPE-PEG 2000 -Biotin prepared in Example 6 is given. It can be seen from Figure 6 that the nanomaterial (AsPh)6@DSPE-PEG 2000-The average hydrated particle size of Biotin in the suspension solution is 199.7 nm.

[0148] (1-3) Biotin-modified nanomaterial (AsPh)6@DSPE-PEG 2000 -Elemental analysis of Biotin

[0149] Figure 5 The Biotin-modified nanomaterial (AsPh)6@DSPE-PEG prepared in Example 6 is given. 2000 -Elemental analysis mapping diagram of Biotin. In the figure, (a) is the co-localization of the distribution of each element in the nanoparticles, (b) is the distribution of arsenic element among them, and (c) is the distribution of carbon element among them. It can be seen that Figure 5 the nanomaterial (AsPh)6@DSPE-PEG synthesized and modified in Example 6 2000 -has a uniform internal elemental distribution of Biotin.

[0150] (2) Hexavalent cyclic organoarsenic compound (AsPh)6 and Biotin-modified nanomaterial (AsPh)6@DSPE-PEG 2000 -In vitro cytotoxicity test of Biotin

[0151] (2-1) Toxicity detection of hexavalent cyclic organoarsenic compound (AsPh)6 against various cell lines. Using sodium arsenite as the positive control group, the experiment was carried out.

[0152] The specific detection steps are as follows:

[0153] 1) After cell counting, the single-cell suspensions of each cell line (human pancreatic cancer cell line BxPC-3, human cervical cancer cell line C33A, human cervical squamous cell carcinoma cell line Siha, mouse colon cancer cell line CT26, human embryonic kidney cell line HEK-293) were inoculated into 96-well plates (10,000 cells / well, 200 μL / well); the culture plates were placed in a 37 °C CO2 incubator and cultured overnight; after 24 hours, the culture medium was changed, and the compound (AsPh)6 prepared in Example 1 was added to each well of the cells, with sodium arsenite as the positive control.

[0154] 2) After each cell was co-incubated with the drugs, namely the compound (AsPh)6 prepared in Example 1 and the positive control sodium arsenite, for 24 hours, the drug-containing culture medium was discarded, and CCK-8 working solution (diluted with serum-free basal medium, 100 μL / well, containing 5 μL / well of CCK-8) was added, and incubated in a CO2 incubator for 3 hours until the absorbance of the negative control (containing cells, CCK-8, without drugs) was 1.

[0155] 3) The 96-well plates were placed in an enzyme-linked immunosorbent assay (ELISA) reader to measure the absorbance of each well at 450 nm.

[0156] 4) Fit the cell growth inhibition curve according to the administration concentration and absorbance, and calculate the half-maximal inhibitory concentration IC 50 of the compound (AsPh)6 against each cell line.

[0157] The toxicity test results of the six-membered cyclic organoarsenic compound (AsPh)6 and the positive control against multiple cell lines are shown in Table 1.

[0158] Table 1 Toxicity test results of the six-membered cyclic organoarsenic compound (AsPh)6 and the positive control in Example 1 against multiple cell lines

[0159]

[0160]

[0161] As can be seen from Table 1, the six-membered cyclic organoarsenic compound (AsPh)6 synthesized in Example 1 has high cytotoxicity against a variety of human and murine cancer cells, while its toxicity to human normal cells is relatively low.

[0162] (2-2) Live / dead staining comparison test of the six-membered cyclic organoarsenic compound (AsPh)6 and the biotinylated nanomaterial (AsPh)6@DSPE-PEG 2000 -Biotin in BxPC-3 cells

[0163] The specific test method is as follows:

[0164] 1) After counting the single-cell suspension of BxPC-3, inoculate it into a confocal glass-bottom culture dish (200,000 cells / well, 1 mL / well); place the culture dish in a 37 °C CO2 incubator and culture overnight; after 24 hours, change the medium, and add PBS buffer (control group), the compound (AsPh)6 synthesized in Example 1, and (AsPh)6@DSPE-PEG 2000 -Biotin synthesized in Example 6 to a final concentration of 2 μM, and incubate in the incubator for 4 hours.

[0165] 2) Discard the drug-containing medium, add Calcein AM and PI staining working solution (2 μM calcein AM and 8 μM PI), incubate at room temperature for 30 minutes, and aspirate the staining working solution to terminate the incubation.

[0166] 3) Observe the cells under a fluorescence microscope.

[0167] The live / dead staining comparison results of the six-membered cyclic organoarsenic compound (AsPh)6 and the biotinylated nanomaterial (AsPh)6@DSPE-PEG 2000 -Biotin in BxPC-3 cells are as followsFigure 7 As shown in the figure. In the figure, (a) is the control group; (b) is the compound of Example 1; (c) is the nanomaterial of Example 6. It can be seen from the figure that the six-membered cyclic organoarsenic compound (AsPh)6 synthesized in Example 1 and the biotin-modified nanomaterial (AsPh)6@DSPE-PEG 2000 -Biotin both have a damaging effect on BxPC-3 cells, and the cell killing effect of (AsPh)6 is more significant at the same concentration.

[0168] (3) Monitoring the uptake and organelle distribution of the six-membered cyclic organoarsenic compound (AsPh)6 and the biotin-modified nanomaterial (AsPh)6@DSPE-PEG 2000 -Biotin in human in situ pancreatic adenocarcinoma cells BxPC-3 in vitro.

[0169] (3-1) Uptake of the six-membered cyclic organoarsenic compound (AsPh)6 and the biotin-modified nanomaterial in human in situ pancreatic adenocarcinoma cells BxPC-3 in vitro

[0170] The specific method is as follows:

[0171] 1) Inoculate BxPC-3 into a cell culture flask and incubate overnight in a 37°C CO2 incubator; after 24 hours, change the medium and add the compound (AsPh)6 of Example 1, (AsPh)6@DSPE-PEG 2000 -Biotin of Example 6, the positive control sodium arsenite, the negative control phenylarsonic acid, and the negative control DPB to a final concentration of 2 μM, and incubate in the incubator for 6 hours.

[0172] 2) Collect the cells and extract the cell nuclei, mitochondria, Golgi apparatus, and endoplasmic reticulum.

[0173] 3) Digest, prepare samples, and determine the arsenic element content in the subcellular organelles by ICP-MS.

[0174] The six-membered cyclic organoarsenic compound (AsPh)6 of Example 1 and the biotin-modified nanomaterial (AsPh)6@DSPE-PEG 2000 -Biotin monitoring results of the uptake and organelle distribution in human in situ pancreatic adenocarcinoma cells BxPC-3 in vitro are respectively as Figure 8 、 Figure 9 shown. In the figure, C6H7AsO3 represents the reaction raw material phenylarsonic acid (as a negative control); NaAsO2 represents sodium arsenite (as a positive control); (AsPh)6 represents the six-membered cyclic organoarsenic compound synthesized in Example 1; DPB represents DSPE-PEG 2000- Biotin (ligand of the nanomaterial, as a negative control); (AsPh)6@DPB represents the biotinylated nanomaterial of Example 6, (AsPh)6@DSPE-PEG 2000 - Biotin. It can be seen from Figure 8 that the hexacyclic organoarsenic compound (AsPh)6 synthesized in Example 1 and the biotinylated nanomaterial (AsPh)6@DSPE-PEG of Example 6 2000 - Biotin have much higher uptake in BxPC-3 cells than the positive control sodium arsenite; among them, at the same concentration, the uptake effect of (AsPh)6 is better than that of (AsPh)6@DSPE-PEG 2000 - Biotin. Figure 9 are the (AsPh)6 of Example 1 and the (AsPh)6@DSPE-PEG of Example 6 2000 - Biotin is a bar graph of the organelle distribution in human in situ pancreatic adenocarcinoma cells BxPC-3 in vitro. In the figure, (a) shows the distribution of the organoarsenic of Example 1 in each organelle after being taken up by the cells; (b) shows the distribution of the nanomaterial of Example 6 in each organelle after being taken up by the cells. It can be seen from Figure 9 that the hexacyclic organoarsenic compound (AsPh)6 synthesized in Example 1 and the biotinylated nanomaterial (AsPh)6@DSPE-PEG of Example 6 2000 - Biotin is mainly distributed in the nucleus and mitochondria in BxPC-3 cells.

[0175] (4) Hexacyclic organoarsenic compound (AsPh)6 and biotinylated nanomaterial (AsPh)6@DSPE-PEG 2000 - Biotin on the intracellular zinc element content and the change of zinc-related protein expression in human in situ pancreatic adenocarcinoma cells BxPC-3 in vitro.

[0176] (4-1) Hexacyclic organoarsenic compound (AsPh)6 and biotinylated nanomaterial (AsPh)6@DSPE-PEG 2000 - Biotin's effect on the intracellular zinc element content in BxPC-3 cells

[0177] The specific method is as follows:

[0178] 1) Inoculate BxPC-3 in a cell culture flask and incubate overnight in a 37°C CO2 incubator; after 24 hours, change the medium and add the compound (AsPh)6 of Example 1, (AsPh)6@DSPE-PEG 2000 - Biotin, the positive control sodium arsenite, and the negative controls phenylarsonic acid and DPB to a final concentration of 2 μM, and incubate in the incubator for 6 hours.

[0179] 2) Collect cells and extract cell nuclei, mitochondria, Golgi apparatuses, and endoplasmic reticulums.

[0180] 3) Nitrolyze, prepare samples, and determine the zinc element content in subcellular organelles by ICP-MS.

[0181] Hexacyclic organic arsenic compound (AsPh)6 and biotin-modified nanomaterial (AsPh)6@DSPE-PEG 2000 -Biotin on the intracellular zinc element content in BxPC-3 cells, the results are as Figure 10 shown. In the figure, (a) shows the comparison of the intracellular zinc element content in the experimental group and each control group; (b) shows the comparison of the zinc element content in mitochondria in the experimental group and each control group; (c) shows the comparison of the zinc element content in endoplasmic reticulums in the experimental group and each control group; (d) shows the comparison of the zinc element content in cell nuclei in the experimental group and each control group; (e) shows the comparison of the zinc element content in cytoplasm in the experimental group and each control group; (f) shows the comparison of the zinc element content in Golgi apparatuses in the experimental group and each control group. It can be seen from the figure that the hexacyclic organic arsenic compound (AsPh)6 synthesized in Example 1 can significantly reduce the zinc content in cells and various organelles; the nanomaterial (AsPh)6@DSPE-PEG 2000 -Biotin synthesized and modified in Example 6 can reduce the zinc element content in mitochondria and endoplasmic reticulums.

[0182] (4-2) Hexacyclic organic arsenic compound (AsPh)6 and biotin-modified nanomaterial (AsPh)6@DSPE-PEG 2000 -Biotin's effect on the expression of zinc-related proteins in BxPC-3 cells Specific implementation method:

[0184] 1) Inoculate BxPC-3 into a cell culture flask and incubate overnight in a 37°C CO2 incubator; after 24 hours, change the medium and add the compound (AsPh)6 of Example 1, (AsPh)6@DSPE-PEG 2000 -Biotin of Example 6, and sodium arsenite as a positive control to a final concentration of 2 μM, and incubate in the incubator for 6 hours.

[0185] 2) Collect cells, extract total proteins and RNAs in the cells, and indicate the expression changes of zinc-related proteins by Western Blot and RT-qPCR.

[0186] The results are as Figure 11As shown in the figure, in the figure, (a) shows the effects of the experimental group and each control group on the content of zinc-related proteins in cells; (b) shows the effects of the experimental group and each control group on the expression of gene SLC39A10; (c) shows the effects of the experimental group and each control group on the expression of gene POLE; (d) shows the effects of the experimental group and each control group on the expression of gene SHPRH; (e) shows the effects of the experimental group and each control group on the expression of gene MBTD1; (f) shows the effects of the experimental group and each control group on the expression of gene WRN; (g) shows the effects of the experimental group and each control group on the expression of gene BIRC5; (h) shows the effects of the experimental group and each control group on the expression of gene UHRF1. It can be seen from the figure that the six-membered cyclic organoarsenic compound (AsPh)6 synthesized in Example 1 and the biotin-modified nanomaterial (AsPh)6@DSPE-PEG 2000 -Biotin can significantly down-regulate the expression of multiple zinc-related proteins in BxPC-3 cells.

[0187] (5) In vivo antitumor effect test of the six-membered cyclic organoarsenic compound (AsPh)6 and the biotin-modified nanomaterial (AsPh)6@DSPE-PEG 2000 -Biotin.

[0188] On the basis of the above cell experiments, a BxPC-3 tumor-bearing mouse model was constructed. After administration for 0, 3, 6, and 10 days, the tumor volume of the mice was monitored. The results are as Figure 12 shown in the figure. In the figure, (a) shows the changes in the tumor volume of the mice in the experimental group and each control group within 15 days; (b) shows the tumor volume of the mice in the experimental group and each control group after treatment (on the 15th day after administration). It was monitored that the six-membered cyclic organoarsenic compound (AsPh)6 in Example 1 and the biotin-modified nanomaterial (AsPh)6@DSPE-PEG 2000 -Biotin experimental groups all showed a very significant antitumor effect.

[0189] (6) Targeting test of the biotin-polymer-modified nanomaterial (AsPh)6@DSPE-PEG 2000 -Biotin on cancer cells.

[0190] Figure 13 This is a comparison of the enrichment of the products (AsPh)6 and (AsPh)6@DSPE-PEG 2000 -Biotin of the present invention in in vivo tumor tissues. From Figure 13 it can be seen that for the mice in test (5), 24 hours after administration, the biotin-polymer-modified nanomaterial (AsPh)6@DSPE-PEG 2000-Biotin is enriched in tumor areas to a much higher degree than unmodified six-membered cyclic organic arsenic compound (AsPh)6.

[0191] Six-membered cyclic organic arsenic compound (AsPh)6 and biotin-modified nanomaterial (AsPh)6@DSPE-PEG of the present invention 2000 -Biotin has obvious cytotoxic effects on various tumor cell lines, but weak toxicity to normal cells; it can target zinc transporters in pancreatic cancer cells, leading to the destruction of zinc homeostasis, thereby inducing tumor cell apoptosis; with the help of the characteristics of biotin and nanomaterials, the tumor accumulation effect was demonstrated in tumor-bearing mice, exerting a targeted anti-tumor effect.

[0192] The above is only a preferred embodiment of the present invention, and the present invention is not limited to the above embodiments. It is understood that other improvements and changes directly derived or associated by those skilled in the art without departing from the spirit and concept of the present invention should be considered to be included in the protection scope of the present invention.

Claims

1. A six-membered cyclic organic arsenic compound, characterized in that: The structural formula of the six-membered cyclic organic arsenic compound is as follows:

2. A method for preparing the six-membered cyclic organic arsenic compound according to claim 1, characterized in that: The steps include: Phenyl arsenic acid is mixed with a reducing agent, and a solvent is added to react to obtain a product 1; the product 1 is recrystallized and freeze-dried to obtain a six-membered cyclic organic arsenic compound.

3. The preparation method according to claim 2, characterized in that: The reducing agent includes at least one of hypophosphorous acid and phosphorous acid; and / or, The mass volume ratio of the phenylarsenic acid to the reducing agent is 10 g:8-13 mL; and / or, The solvent comprises at least one of methanol, ethanol and isopropanol; and / or, The ethanol is anhydrous ethanol; and / or, The volume ratio of the solvent to the reducing agent is 1:1 to 4:

1.

4. The preparation method according to claim 2, characterized in that: The reaction is carried out under nitrogen protection at 70-80° C. with stirring for 3-5 hours; and / or, The recrystallization solution is a mixed solution of benzene and chlorobenzene, wherein the volume ratio of the benzene to the chlorobenzene is 3 to 5:1; or, the recrystallization solution is a mixed solution of chloroform and n-pentane, wherein the volume ratio of the n-pentane to the chlorobenzene is 3 to 5:1; and / or, The recrystallization conditions are 2-8° C. and standing for 12-24 hours.

5. The preparation method according to claim 2, characterized in that: The freeze drying temperature is -40°C to -80°C, and the time is 24 to 96 hours.

6. A biotin-modified nanomaterial, characterized in that: The nanomaterial comprises the six-membered cyclic organic arsenic compound according to claim 1, or the six-membered cyclic organic arsenic compound prepared by the preparation method according to any one of claims 2-5.

7. The biotin-modified nanomaterial according to claim 6, characterized in that: The nano material is obtained by dissolving a six-membered ring organic arsenic compound in solvent I to obtain a six-membered ring organic arsenic compound solution, then adding a phospholipid polyethylene glycol biotin solution, ultrasonically dispersing, and rotary evaporating.

8. The biotin-modified nanomaterial according to claim 7, characterized in that: The solvent I comprises at least one of n-hexane, dichloromethane, chloroform, methanol, ethanol, isopropanol and dimethyl sulfoxide; and / or, The concentration of the six-membered cyclic organic arsenic compound solution is 1 to 1.5 mg / mL; The phospholipid polyethylene glycol biotin solution is obtained by mixing phospholipid polyethylene glycol biotin and solvent II; and / or, The solvent II comprises at least one of water, phosphate buffer and physiological saline; and / or, The mass ratio of the six-membered ring organic arsenic to the phospholipid polyethylene glycol biotin is 1-2:1-2; and / or, The volume ratio of the solvent I to the solvent II is 1:1-2; and / or, The phospholipid polyethylene glycol biotin is distearoylphosphatidyl acetamide-polyethylene glycol 2000-biotin.

9. The biotin-modified nanomaterial according to claim 7, characterized in that: The power of the ultrasound is 100-400W, and the time is 60-90min; The temperature of the rotary evaporation is ≤40°C.

10. An anti-tumor drug, characterized in that: It comprises the six-membered cyclic organic arsenic compound according to claim 1, or the six-membered cyclic organic arsenic compound according to any one of claims 2-5, or the biotin according to any one of claims 6-8.

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