CN114989161A - C-MYC transcription inhibitor and preparation method and application thereof - Google Patents

Abstract

The invention discloses a c-MYC transcription inhibitor, a preparation method and an application thereof. The c-MYC transcription inhibitor disclosed by the invention is good in stability, convenient to store, small in toxic and side effects and good in anti-tumor effect, and particularly can be specifically combined in vitro and in vivo and stabilize a c-MYC G-quadruplex, so that the transcription of a human liver cancer cell HepG2c-MYC is inhibited, the migration of the human liver cancer cell HepG2 is inhibited, and the growth of the human liver cancer cell HepG2 in vivo is finally inhibited. The preparation method of the c-MYC transcription inhibitor is simple in preparation, low in cost and suitable for large-scale production.

Description

A kind of c-MYC transcription inhibitor and its preparation method and application

technical field

The invention relates to the field of medicine, in particular to a c-MYC transcription inhibitor and a preparation method and application thereof.

Background technique

Malignant tumor (also known as cancer) is one of the major diseases that endanger human life and health, and it is also a major challenge facing human beings in the field of medical and health care. Studies have found that more than 90% of malignant tumors can be observed in single or multiple gene persistent changes. Among them, the mutation or overexpression of oncogenes is the most frequent cellular event in malignant tumors. The proto-oncogene c-MYC is one of the most studied oncogenes and one of the most frequently activated oncogenes. c-MYC belongs to the MYC family, and its expression directly and indirectly regulates many important life processes such as cell proliferation, growth, differentiation, metabolism and apoptosis, and is closely related to the occurrence and development of more than 20% of malignant tumors. A large amount of research evidence has shown that the proto-oncogene c-MYC is located at the intersection of many growth-promoting signal transduction pathways, and the abnormal expression of c-MYC can induce tumor formation and maintain tumor growth. In addition, the expression product of c-MYC, MYC oncoprotein, can also be used as a multifunctional transcription factor, alone or in combination with other transcription factors to participate in the expression and regulation of genes related to various basic biological processes, and promote the occurrence and growth of tumors. At present, studies have shown that the occurrence and development of malignant tumors can be significantly inhibited by reducing the expression of c-MYC, which provides a theoretical basis for the development of anti-tumor drugs targeting c-MYC and MYC proteins. However, the inherent disordered nature of MYC proteins makes it difficult to design specifically targeted small molecules. Therefore, there are currently two main strategies for controlling MYC: interfering with the expression and function of MYC, and directly inhibiting the transcription of the oncogene c-MYC. Direct inhibition of the transcription of the oncogene c-MYC is currently a widely studied tumor suppressor strategy. Among them, the upstream regulatory element of c-MYC gene is the main way to inhibit the transcription of c-MYC.

G-quadruplex is an atypical nucleic acid secondary structure. During gene transcription, if a G-quadruplex is formed in the NHE III1 region of the nucleic acid hypersensitivity element upstream of the P1 promoter region of c-MYC, it can hinder the The proximity of RNA polymerase, thereby inhibiting the transcription of c-MYC. Compounds that specifically bind to G-quadruplex can maintain the gene silencing function of G-quadruplex by stabilizing the G-quadruplex structure formed on the c-MYC promoter, resulting in down-regulation of c-MYC expression. Therefore, the development of novel c-MYC transcriptional inhibitors has great significance and broad application prospects in the treatment of cancer.

SUMMARY OF THE INVENTION

In order to overcome the above-mentioned problems in the prior art, one of the objects of the present invention is to provide a c-MYC transcription inhibitor, which can specifically bind to and stabilize c-MYC G-tetrakis in vitro and in vivo Chain body, thereby inhibiting the transcription of human hepatoma cell HepG2 c-MYC and inhibiting the migration of human hepatoma cell HepG2, and finally inhibiting the growth of human hepatoma cell HepG2 in vivo.

Another object of the present invention is to provide a method for preparing the above-mentioned c-MYC transcription inhibitor.

The third object of the present invention is to provide a G-quadruplex ligand.

The fourth object of the present invention is to provide an antitumor drug.

The fifth object of the present invention is to provide the application of the above-mentioned c-MYC transcription inhibitor in the preparation of a medicament for preventing or treating tumors.

In order to achieve the above object, the technical scheme adopted by the present invention is:

A first aspect of the present invention is to provide a c-MYC transcription inhibitor, comprising a compound represented by any one of formulae (I) to (IV) or a pharmaceutically acceptable salt, isomer and solvate thereof;

Wherein, A ^- is N methylation anion, iodide, bromide, p-toluenesulfonate, trifluoroacetate, perchlorate, tetrafluoroborate, methylsulfate or trifluoromethanesulfonate;

R ₁ and R ₂ are independently selected from fluorine, chlorine, bromine, hydrogen, amino or amine substituents;

_R3 is independently selected from an aromatic ring, a substituted aromatic ring, or an aromatic heterocyclic ring.

Preferably, in formula (I)～(IV):

A ^- is iodide, bromide, p-toluenesulfonate, trifluoroacetate, perchlorate, tetrafluoroborate, methyl sulfate or trifluoromethanesulfonate;

R1 and R2 are independently selected from fluorine, hydrogen, amino or amine substituents;

R3 is independently selected from aromatic rings, substituted aromatic rings or aromatic heterocycles.

Preferably, in formula (I)～(IV):

A ^- is iodide, bromide, p-toluenesulfonate, trifluoroacetate, perchlorate, tetrafluoroborate, methyl sulfate or trifluoromethanesulfonate;

R1 and R2 are independently selected from fluorine, hydrogen, amino or amine substituents;

R3 is independently selected from

Preferably, in formula (I)～(IV):

A ^- is iodide ion;

Both R1 and R2 are hydrogen;

R3 is independently selected from

A second aspect of the present invention is to provide a method for preparing the c-MYC transcription inhibitor provided by the first aspect of the present invention, comprising the following steps:

为原料合成式(I)所示的化合物或式(II)所示的化合物；以

为原料合成式(III)所示的化合物或式(IV)所示的化合物；by

As the raw material, the compound represented by the formula (I) or the compound represented by the formula (II) is synthesized; with

For the raw material to synthesize the compound shown in formula (III) or the compound shown in formula (IV);

The preparation method of the compound shown in the formula (I) comprises the following steps:

与硒、溴化亚铜混合反应，制得

然后将

与次磷酸反应得到

再与乙酰丙酮反应，制得

然后将

与

反应，制得所述式(I)所示的化合物；Will

Mixed reaction with selenium and cuprous bromide to obtain

followed by

react with hypophosphorous acid

Then react with acetylacetone to obtain

followed by

and

reaction to obtain the compound represented by the formula (I);

or,

The preparation method of the compound shown in the formula (III) comprises the following steps:

与硒、溴化亚铜混合反应，制得

然后将

与三丁基膦、乙酸反应，制得

然后将

与

反应，制得所述式(III)所示的化合物；Will

Mixed reaction with selenium and cuprous bromide to obtain

followed by

Reaction with tributylphosphine and acetic acid to obtain

followed by

and

reaction to obtain the compound represented by the formula (III);

or,

The preparation method of the compound shown in the formula (II) or the compound shown in the formula (IV) comprises the following steps:

与甲基化试剂反应，制得

然后将

与

反应，制得式(II)所示的化合物或式(IV)所示的化合物；Will

react with methylating reagents to obtain

followed by

and

reaction to obtain the compound represented by the formula (II) or the compound represented by the formula (IV);

Or, the preparation method of the compound shown in the formula (II) or the compound shown in the formula (IV) comprises the following steps:

The compound represented by the formula (I) or the compound represented by the formula (III) is reacted with a methylating reagent to obtain the compound represented by the formula (II) or the compound represented by the formula (IV);

Wherein, A ^- , R1, R2, and _R3 are as defined above.

Preferably, the methylating agent is CH ₃ A, and the A ^- is N methylation anion, iodide, bromide, p-toluenesulfonate, trifluoroacetate, perchlorate, tetrafluoroborate, Methyl sulfate or triflate.

Preferably, the methylating reagent is methyl iodide, methyl bromide, methyl p-toluenesulfonate, methyl trifluoromethanesulfonate, methyl perchlorate, methyl tetrafluoroborate, methyl methosulfate or trifluoromethane Methyl methanesulfonate.

The third aspect of the present invention is to provide a G-quadruplex ligand, comprising at least one of the compounds represented by formulae (I) to (IV);

Wherein, A ^- , R1, R2, and R3 are as defined above.

The fourth aspect of the present invention is to provide an anti-tumor drug, including the c-MYC transcription inhibitor provided by the first aspect of the present invention.

Preferably, the tumor comprises liver cancer, colon cancer or colon adenocarcinoma.

Preferably, in the anti-tumor drug, the content of c-MYC transcription inhibitor is 0.05-50 wt %; further preferably, in the anti-tumor drug, the content of c-MYC transcription inhibitor is 1-50 wt %; Further preferably, in the anti-tumor drug, the content of c-MYC transcription inhibitor is 10-50 wt%.

The fifth aspect of the present invention is to provide the use of a c-MYC transcription inhibitor in the preparation of a medicament for preventing or treating tumors.

Preferably, the tumor includes liver cancer, colon cancer, colon adenocarcinoma.

The beneficial effects of the present invention are as follows: the c-MYC transcription inhibitor in the present invention has good stability, is easy to store, has few toxic and side effects, and has good anti-tumor effect. Specifically, the c-MYC transcription inhibitor can be specific in vitro and in vivo. The binding and stabilization of c-MYC G-quadruplex, thereby inhibiting the transcription of human hepatoma cell HepG2 c-MYC and inhibiting the migration of human hepatoma cell HepG2, finally inhibited the growth of human hepatoma cell HepG2 in vivo.

The preparation method of the c-MYC transcription inhibitor in the present invention is simple in preparation, low in cost, and suitable for large-scale production.

Description of drawings

FIG. 1 is a graph showing the stabilization effect of m-Se3 on c-MYC G-quadruplex in Example 6 of the present invention.

FIG. 2 is a graph showing the effect of the c-MYC transcription inhibitor on G-quadruplex in Examples 1 to 8 of the present invention.

FIG. 3 is a graph showing the effect of m-Se3 on transcription inhibition of c-MYC gene in Example 6 of the present invention.

FIG. 4 is a graph showing the effect of m-Se3 on the proliferation inhibition of HepG2 cells at different concentrations in Example 6 of the present invention.

FIG. 5 is a graph showing the effect of m-Se3 on the migration inhibition of HepG2 cells at different concentrations in Example 6 of the present invention.

6 is a graph showing that m-Se3 in Example 6 of the present invention inhibits the growth of hepatoma cells HepG2 in vivo.

FIG. 7 is a graph showing the test results of the effect of m-Se3 on the body weight of mice in Example 6 of the present invention.

Detailed ways

The specific implementation of the present invention will be further described in detail below with reference to the accompanying drawings and examples, but the implementation and protection of the present invention are not limited thereto. It should be pointed out that, if there are any processes that are not described in detail below, those skilled in the art can implement or understand them with reference to the prior art. If the reagents or instruments used do not indicate the manufacturer, they are regarded as conventional products that can be purchased in the market.

Example 1

The structural formula of the c-MYC transcriptional inhibitor in this example is as follows:

where R1 is H, R2 is H, and _R3 is

The c-MYC transcription inhibitor in this example is prepared by the following preparation method, which specifically includes the following steps:

(1) Synthesis of bis(2-aminophenyl)-diselenide

The reaction formula is:

2-iodoaniline (5.0g, 22.8mmol), selenium powder (5.4g, 68.5mmol), cuprous bromide (0.7g, 4.6mmol) and potassium hydroxide (2.6g, 45.6mmol) were added to a three-necked flask Under the protection of inert gas Ar, 10 ml of anhydrous DMSO was added, and the reaction was carried out at 120 °C in an oil bath for 48 h. After the reaction of the raw material 2-iodoaniline was completed, it was cooled to room temperature, diluted with excess saturated sodium carbonate solution, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and concentrated by rotary evaporation. Purification by silica gel column chromatography (eluent is a mixture of petroleum ether and dichloromethane in a volume ratio of 5:1) to obtain an orange oily liquid with a yield of 25%.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.38 (d, J=7.8 Hz, 2H), 7.12 (t, J=7.6 Hz, 2H), 6.72 (d, J=8.0 Hz, 2H), 6.65 ( t, J=7.5Hz, 2H), 3.77 (br, 4H).

(2) Synthesis of 2-methylbenzoselenazole

Reaction formula:

Bis(2-aminophenyl)-diselenide (1.0 g, 2.9 mmol) was suspended in 6 ml of glycerol and placed in an oil bath at 90°C under the protection of inert gas Ar gas. While stirring, 3 ml of hypophosphorous acid (50 wt.% aqueous solution) was added dropwise, and the reaction was carried out at 90° C. for 30 min. When it was observed that the yellow solution became colorless, acetylacetone (0.6 g, 5.8 mmol) was added, and the reaction was carried out at 90° C. for 6 h. After the reaction of the intermediate raw materials was completed, excess water was added to dilute, and ethyl acetate was extracted. The organic phase was dried over anhydrous sodium sulfate, and concentrated by rotary evaporation. Purified by silica gel column chromatography (eluent: a mixture of petroleum ether and dichloromethane in a volume ratio of 100:1) to obtain a pale yellow oily liquid with a yield of 89%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.99 (d, J=8.1 Hz, 1H), 7.86 (d, J=7.9 Hz, 1H), 7.44 (t, J=7.7 Hz, 1H), 7.29 (t , J=7.8Hz, 1H), 2.87(s, 3H).

(3) Synthesis of c-MYC transcription inhibitor

Reaction formula:

2-Methylbenzoselenazole (215.7 mg, 1.1 mmol) and N-ethylcarbazole-3-carbaldehyde (50 mg, 0.22 mmol) were dissolved in 0.5 ml DMSO, and 0.25 ml 50% KOH was slowly added dropwise with stirring The solution was reacted at room temperature for 24h. A small amount of ice water was added, and the pH was adjusted to 7-8 with 1 mol/L HCl solution. Filtration under reduced pressure, the filter cake was washed three times with ice ethanol, and dried under vacuum to obtain a brownish yellow solid (43.1 mg, 48.0%), which was the c-MYC transcription inhibitor in this example, denoted as Se1. Purity by HPLC was 95.2%, HRMS (ESI) m/z: _calcd for _C23H18N2Se , [M+H] ⁺ _403.0709 , mass spectrum peak of 403.0698 was found.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.31 (s, 1H), 8.13 (d, J=7.7 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.90 (d, J=7.8 Hz ,1H),7.75(dd,J＝8.5,1.2Hz,1H),7.61(d,J＝15.9Hz,1H),7.47(dt,J＝18.2,8.3Hz,5H),7.29(t,J＝ 7.4Hz, 2H), 4.39 (q, J=7.2Hz, 2H), 1.46 (t, J=7.2Hz, 3H);

¹³ C NMR(126MHz,CDCl ₃ )δ172.19,155.69,140.88,140.84,140.57,136.97,126.66,126.45,126.35,125.29,125.15,124.85,124.29,123.57,122.98,122.40,120.70,120.61,119.67,109.14,108.97 , 37.88, 13.99.

Example 2

The structural formula of the c-MYC transcriptional inhibitor in this example is as follows:

where R1 is H, R2 is H, and _R3 is

The c-MYC transcription inhibitor in this example is prepared by the following preparation method, which specifically includes the following steps:

(1) Synthesis of N-(3-(N,N-dimethylamino)propyl)-carbazole-3-carbaldehyde

In an ice bath environment, carbazole (500 mg, 2.99 mmol) was dissolved in 5 mL of anhydrous DMF and added to a 15 mL pressure-resistant tube, then NaH (120 mg, 4.95 mmol) was added and stirred for 1 h, and then N,N-dimethylform was added dropwise yl-3-chloropropylamine (542.37 mg, 4.48 mmol) was stirred for 10 min. Subsequently, the temperature was raised to 60 °C for 16 h, and after TLC (thin layer chromatography) detected the completion of the reaction, it was quenched with 20 ml of ice-water mixture, extracted with ethyl acetate (EA), and purified by silica gel column chromatography to obtain N-(3-(N-(3-(N). , N-dimethylamino)propyl)-carbazole (632 mg, 80%).

In an ice bath environment, anhydrous DMF (400 mg, 5.4 mmol) was added to a three-necked flask, protected by Ar, then POCl ₃ (700 mg, 4.56 mmol) was added dropwise, stirred for 30 min, and moved to room temperature for 1 h. Next, N-(3-(N,N-dimethylamino)propyl)-carbazole (486.7 mg, 1.93 mmol) was added to the mixed system for reaction at room temperature for 30 min, and then the temperature was raised to 60 °C for 16 h. TLC detected that the reaction was complete. , cooled to room temperature and quenched by adding 20ml of ice water, adjusted to neutral pH, extracted with EA, and purified by silica gel column chromatography to obtain N-(3-(N,N-dimethylamino)propyl)-carbazole-3 -Formaldehyde (178 mg, 35%).

1H NMR(400MHz, DMSO-d6)δ10.06(s,1H),8.76(d,J=1.2Hz,1H),8.29(d,J=7.7Hz,1H),8.00(dd,J=8.6, 1.5Hz,1H),7.78(d,J=8.6Hz,1H),7.70(d,J=8.2Hz,1H),7.57-7.52(m,2H),7.34-7.29(m,2H),4.48( t, J=6.8Hz, 2H), 2.18 (t, J=6.8Hz, 3H), 2.11 (s, 6H), 1.92 (p, J=6.8Hz, 4H).

(2) Synthesis of c-MYC transcription inhibitor

2-Methylbenzoselenazole (350mg, 1.78mmol) and N-(3-(N,N-dimethylamino)propyl)-carbazole-3-carbaldehyde (100mg, 0.36mmol) were dissolved in 0.5ml In DMSO, 0.25 ml of 50% KOH solution was slowly added dropwise while stirring, and the reaction was carried out at room temperature for 24 h. Add a small amount of ice water, adjust the pH to 7-8 with 1 mol/L HCl solution, and spin dry. HPLC purification yielded a yellow solid (6.1 mg, 3.7%), which prepared the c-MYC transcription inhibitor in this example, designated as Se2. Purity by HPLC was 95.7%, HRMS (ESI) m/z: calcd for C26H25N3Se, [ _M +H] ⁺ _460.1288 , a mass spectrum peak of _460.1289 was found.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.65 (s, 1H), 8.24 (d, J=7.8Hz, 1H), 8.13 (d, J=7.9Hz, 1H), 7.96 (d, J= 8.6Hz, 2H), 7.79–7.66 (m, 4H), 7.56–7.47 (m, 2H), 7.37–7.28 (m, 2H), 4.55–4.49 (m, 2H), 3.26–3.10 (m, 2H) ,2.76(s,6H),2.18(dd,J=8.5,6.3Hz,2H);

¹³ C NMR(101MHz,DMSO-d ₆ )δ153.79,140.51,140.35,140.31,139.41,137.88,126.95,126.57,126.46,125.61,125.28,124.07,123.86,122.94,122.25,121.32,120.70,119.90,119.71,109.99 , 109.66, 54.60, 42.48, 42.48, 40.15, 23.92.

Example 3

The structural formula of the c-MYC transcriptional inhibitor in this example is as follows:

where R1 is H, R2 is H, and _R3 is

The c-MYC transcription inhibitor in this example is prepared by the following preparation method, which specifically includes the following steps:

2-Methylbenzoselenazole (176.5 mg, 0.9 mmol) and N-benzylcarbazole-3-carbaldehyde (50 mg, 0.18 mmol) were dissolved in 0.5 ml DMSO, and 0.25 ml 50% KOH was slowly added dropwise with stirring The solution was reacted at room temperature for 24h. A small amount of ice water was added, and the pH was adjusted to 7-8 with 1 mol/L HCl solution. Filtration under reduced pressure, the filter cake was washed three times with ice ethanol, and dried in vacuo to obtain a khaki solid (65.8 mg, 81.0%), which was the c-MYC transcription inhibitor in this example, denoted as Se3. The purity of the product by HPLC was 95.6%; HRMS (ESI) m/z: _calcd for _C28H20N2Se , [ _M +H] ⁺ 465.0866, mass spectrum peak of 465.0874 found.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.33 (s, 1H), 8.15 (d, J=7.7 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.90 (d, J=7.8 Hz ,1H),7.70(d,J＝8.6Hz,1H),7.59(d,J＝15.9Hz,1H),7.46(dt,J＝8.3,4.1Hz,3H),7.40(t,J＝9.4Hz ,3H),7.33–7.27(m,4H),7.15(d,J=6.2Hz,2H),5.53(s,2H);

¹³ C NMR(126MHz,CDCl ₃ )δ172.07,155.75,141.58,141.32,140.60,137.05,136.82,129.01,129.01,127.79,127.17,126.60,126.52,126.52,126.46,125.39,125.33,124.86,124.36,123.73,123.07 , 122.71, 120.68, 120.51, 120.10, 109.64, 109.45, 46.88.

Example 4

The structural formula of the c-MYC transcriptional inhibitor in this example is as follows:

where A is I, R1 is H, R2 is H, and _R3 is

The c-MYC transcription inhibitor in this example is prepared by the following preparation method, which specifically includes the following steps:

(1) Synthesis of N-methyl 2-methylbenzoselenazole iodide

2-Methylbenzoselenazole (480 mg, 2.45 mmol) was dissolved in 200 μL of acetonitrile, methyl iodide (855 μL, 13.7 mmol) was added, and the reaction was refluxed at 80° C. for 24 h in the dark in the dark. The reaction was monitored by thin layer chromatography. When there is no raw material remaining in the system, it is cooled to room temperature. After the excess methyl iodide was volatilized, excess absolute ethanol was added, and the solid was uniformly dispersed in ethanol by ultrasonication, filtered under reduced pressure, and the filter cake was washed three times with absolute ethanol, and dried in vacuo to obtain N-methyl 2-methylbenzoselenide. azole iodide.

1H NMR(400MHz,Methanol-d4)δ8.36(d,J=8.1Hz,1H),8.24(d,J=8.5Hz,1H),7.89(t,J=7.9Hz,1H),7.76(t , J=7.7Hz, 1H), 4.26(s, 3H), 3.24(s, 3H).

(2) Synthesis of c-MYC transcription inhibitor

N-methyl 2-methylbenzoselenazole iodide (100 mg, 0.47 mmol) and 1.1 times the equivalent of N-ethylcarbazole-3-carbaldehyde were dissolved in 0.5 ml of ethanol and reacted at 80 °C for 24 h. The reaction was monitored by thin layer chromatography. When no intermediate raw materials remained in the reaction system, the reaction system was cooled to room temperature, and a solid was precipitated. Filtration under reduced pressure, the filter cake was washed three times with ice ethanol, and dried in vacuo to obtain a red solid (127 mg, 56.0%), which was the c-MYC transcription inhibitor in this example, denoted as m-Se1. Purity by HPLC was 99.6%, HRMS (ESI) m/z: _calcd for _C24H21N2Se ⁺ , [MI] ⁺ _417.0866 , mass spectrum peak of 417.0866 was found.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.95 (s, 1H), 8.45 (dd, J=15.6, 11.7 Hz, 2H), 8.23 (d, J=8.2 Hz, 2H), 8.16 (d, J=8.4Hz, 1H), 8.04 (d, J=15.4Hz, 1H), 7.83–7.77 (m, 2H), 7.71 (d, J=8.2Hz, 1H), 7.67 (t, J=7.8Hz, 1H), 7.56(t, J=7.7Hz, 1H), 7.34(t, J=7.5Hz, 1H), 4.52(q, J=6.9Hz, 2H), 4.34(s, 3H), 1.37(t, J=7.1Hz, 3H);

¹³ C NMR(126MHz,DMSO-d ₆ )δ180.75,152.45,143.30,142.17,140.27,128.96,128.64,128.24,127.65,127.02,126.81,125.55,123.80,122.92,122.21,120.62,120.26,117.95,113.01,110.05 , 110.05, 37.41, 37.41, 13.83.

Example 5

The structural formula of the c-MYC transcriptional inhibitor in this example is as follows:

where A is I, R1 is H, R2 is H, and _R3 is

The c-MYC transcription inhibitor in this example is prepared by the following preparation method, which specifically includes the following steps:

N-methyl 2-methylbenzoselenazole iodide (100 mg, 0.47 mmol) was combined with 1.1 equivalents of N-(3-(N,N-dimethylamino)propyl)-carbazole-3-carbaldehyde Dissolve in 0.5ml of ethanol and react at 80°C for 24h. The reaction was monitored by thin layer chromatography. When no intermediate raw materials remained in the reaction system, the reaction system was cooled to room temperature, and a solid was precipitated. Filtration under reduced pressure, the filter cake was washed three times with ice ethanol, and a red solid was obtained after vacuum drying, which was the c-MYC transcription inhibitor in this example, denoted as m-Se2. Purity by HPLC was 99.1%, HRMS (ESI) m/z: calcd for _C27H28N3Se +, _[ MI]+ _474.1445 , mass spectrum peak of 474.1428 was found.

¹ H NMR(400MHz, DMSO-d6)δ8.97(s,1H),8.42(dd,J=11.5,2.8Hz,2H),8.24(t,J=7.5Hz,3H),8.06(d,J =15.9Hz,1H),7.91-7.82(m,2H),7.78(t,J=8.0Hz,2H),7.63-7.55(m,1H),7.38(t,J=7.3Hz,1H),4.61 – 4.51(m, 2H), 4.38(s, 3H), 3.16 – 3.05(m, 2H), 2.70(s, 6H), 2.21 – 2.11(m, 2H);

¹³ C NMR(101MHz,DMSO-d6)δ172.01,150.46,142.54,142.05,140.63,129.33,128.39,128.15,127.44,127.00,125.54,124.52,124.12,123.67,123.08,122.33,120.82,120.55,116.82,116.58, 110.45, 54.23, 42.21, 42.21, 40.15, 38.97, 23.71.

Example 6

The structural formula of the c-MYC transcriptional inhibitor in this example is as follows:

where A is I, R1 is H, R2 is H, and _R3 is

The c-MYC transcription inhibitor in this example is prepared by the following preparation method, which specifically includes the following steps:

N-methyl-2-methylbenzoselenazole iodide (100 mg, 0.47 mmol) and 1.1 times the equivalent of N-benzylcarbazole-3-carbaldehyde were dissolved in 0.5 ml of ethanol and reacted at 80 °C for 24 h. The reaction was monitored by thin layer chromatography. When no intermediate raw materials remained in the reaction system, the reaction system was cooled to room temperature, and a solid was precipitated. Filtration under reduced pressure, and the filter cake was washed with ice ethanol to obtain a red solid (126.7 mg, 55.9%), which was the c-MYC transcription inhibitor in this example, denoted as m-Se3. Purity by HPLC was 98.6%; HRMS (ESI) m/z: _calcd for _C29H23N2Se ⁺ , [MI] ⁺ _479.1023 , mass spectrum peak of 479.1009 was found.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.98 (s, 1H), 8.46 (dd, J=15.2, 11.8 Hz, 2H), 8.28-8.15 (m, 3H), 8.06 (d, J=15.4 Hz, 1H), 7.87(d, J=8.7Hz, 1H), 7.83–7.77(m, 1H), 7.70(dd, J=18.3, 8.0Hz, 2H), 7.53(t, J=7.7Hz, 1H) ), 7.36(t, J=7.4Hz, 1H), 7.33–7.21(m, 5H), 5.76(s, 2H), 4.34(s, 3H);

¹³ C NMR(101MHz,DMSO-d ₆ )δ180.89,152.28,143.36,142.83,140.88,137.20,129.07,128.71,128.69,128.69,128.32,127.76,127.49,127.04,126.96,126.82,126.82,125.96,123.71,123.05 , 122.31, 120.62, 120.57, 118.07, 113.38, 110.58, 110.55, 45.93, 37.43.

Example 7

The structural formula of the c-MYC transcriptional inhibitor in this example is as follows:

where _R3 is

The c-MYC transcription inhibitor in this example is prepared by the following preparation method, which specifically includes the following steps:

(1) Synthesis of bis(1-amino-2-naphthyl) diselenide

Reaction formula:

Dissolve 1-amino-2-bromonaphthalene (5.0g, 22.5mmol), selenium powder (5.3g, 67.5mmol), cuprous bromide (0.6g, 4.5mmol) and potassium hydroxide (2.5g, 45.0mmol) In 15 ml of anhydrous DMSO, under the protection of inert gas, the reaction was carried out in an oil bath at 120 °C for 48 h. The reaction was monitored by thin layer chromatography. After the reaction of the raw material 1-amino-2-bromonaphthalene is complete, it is cooled to room temperature, diluted with excess saturated sodium carbonate solution, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and concentrated by rotary evaporation. Purified by silica gel column chromatography (eluent: a mixture of petroleum ether and dichloromethane in a volume ratio of 30:1) to obtain a black-purple solid with a yield of 19%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.81-7.71 (m, 4H), 7.49 (d, J=8.6 Hz, 2H), 7.45 (dq, J=6.7, 3.5 Hz, 4H), 7.15 (d, J=8.5Hz, 2H), 4.86 (br, 4H).

(2) Synthesis of 2-methyl-β-naphthoselenazole

Reaction formula:

Dissolve bis(1-amino-2-naphthyl) diselenide (500 mg, 1.1 mmol) in 6.8 ml of anhydrous toluene, add tributylphosphine (724 mg, 3.3 mmol) under the protection of inert gas, and stir at room temperature for 5 min. Acetic acid (204 mg, 3.3 mmol) was added, and the reaction was carried out under microwave irradiation (100 °C, 100 W) for 2 h. It was diluted by adding excess saturated sodium carbonate solution and extracted three times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, and concentrated by rotary evaporation. Purification by silica gel column chromatography (eluent is a mixture of petroleum ether and dichloromethane in a volume ratio of 50:1) to obtain a yellow oily liquid with a yield of 84%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.81 (d, J=8.0 Hz, 1H), 7.92 (dd, J=7.8, 6.4 Hz, 2H), 7.75 (d, J=8.7 Hz, 1H), 7.67 –7.61(m,1H),7.59–7.54(m,1H),2.98(s,3H).

(3) Synthesis of c-MYC transcription inhibitor

Reaction formula:

2-Methyl-β-naphthoselenazole (270.8 mg, 1.1 mmol) and N-ethylcarbazole-3-carbaldehyde (50 mg, 0.22 mmol) were dissolved in 0.5 ml DMSO, and 0.25 ml was slowly added dropwise with stirring 50% KOH solution, react at room temperature for 24h. A small amount of ice water was added, and the pH was adjusted to 7-8 with 1 mol/L HCl solution. Filtration under reduced pressure, the filter cake was washed three times with ice ethanol, and dried in vacuo to obtain a yellow solid (50.2 mg, 54.7%), denoted as p-Se1. 96.0% purity by HPLC, HRMS (ESI) m/z: _calcd for _C27H20N2Se , [ _M +H] ⁺ 453.0866, mass spectrum peak of 453.0858 found.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.88 (d, J=8.2 Hz, 1H), 8.35 (s, 1H), 8.14 (d, J=7.6 Hz, 1H), 7.96-7.91 (m, 2H) ,7.76(dd,J＝12.7,8.8Hz,2H),7.67(d,J＝7.5Hz,1H),7.65(s,1H),7.59(s,1H),7.56(d,J＝6.8Hz, 1H), 7.54–7.48 (m, 2H), 7.43 (d, J=8.4Hz, 2H), 7.30 (d, J=7.4Hz, 1H), 4.39 (dd, J=14.1, 7.0Hz, 2H), 1.47(t,J=7.1Hz,3H);

¹³ C NMR(126MHz,CDCl ₃ )δ172.08,151.44,140.80,140.60,139.59,134.39,132.32,129.81,128.14,126.97,126.32,125.97,125.80,125.23,124.90,124.89,123.62,123.05,122.87,122.06,120.72 , 120.40, 119.64, 109.11, 108.97, 37.89, 14.00.

Example 8

The structural formula of the c-MYC transcriptional inhibitor in this example is as follows:

where A is I and _R is

The c-MYC transcription inhibitor in this example is prepared by the following preparation method, which specifically includes the following steps:

The p-Se1 (50 mg, 0.11 mmol) was dissolved in 0.5 ml of acetonitrile, iodomethane (62.4 mg, 0.44 mmol) was added rapidly, and the reaction was refluxed at 80° C. for 24 h. Cooled to room temperature, after the excess methyl iodide was evaporated, filtered under reduced pressure, the filter cake was washed with ether three times, washed with ice ethanol once, and dried under vacuum to obtain a reddish-brown solid (28.9 mg, 56.0%), denoted as mp-Se1. The purity obtained by HPLC was 99.3%; HRMS (ESI) m/z: calcd for C ₂₈ H ₂₃ N ₂ Se ⁺ , [MI] ⁺ 467.1023, a mass spectrum peak of 467.0998 was found.

The reaction formula is:

¹ H NMR (400MHz, DMSO-d ₆ )δ8.92(s, 1H), 8.90(d, J=8.6Hz, 1H), 8.47-8.40(m, 2H), 8.26-8.20(m, 3H), 8.17(d,J＝8.7Hz,1H),8.09(d,J＝15.3Hz,1H),7.88–7.76(m,3H),7.69(d,J＝8.3Hz,1H),7.54(t,J ＝7.6Hz, 1H), 7.34(t, J＝7.4Hz, 1H), 4.75(s, 3H), 4.49(dd, J＝13.7, 6.6Hz, 2H), 1.36(t, J＝7.0Hz, 3H) );

¹³ C NMR(101MHz,DMSO-d ₆ )δ180.59,151.31,142.00,140.26,138.87,133.71,130.27,129.85,129.05,128.07,127.93,127.29,126.77,125.72,123.90,123.48,123.13,122.91,122.64,122.21 , 120.59, 120.19, 113.48, 110.01, 110.00, 43.65, 37.38, 13.81.

Performance Testing:

(1) Stabilization of c-MYC G-quadruplex

The DNA solution (c-MYC pu22 nucleic acid solution) was diluted to 2 μmol/L with G-quadruplex buffer (10mmol/L Tris-HCl buffer, pH 7.4, 2mmol/L KCl) to obtain two groups of c- MYC pu22 nucleic acid solution solution, one group was used as the control group, and the other group was added with m-Se3 to make the concentration 10μmol/L, as the experimental group, and then the two groups of solutions were added to the quartz cuvette and placed in the circular dichroism inside the instrument. Set the instrument program to collect spectra in the range of 230-330nm at a scanning speed of 0.5s/nm, with a bandwidth of 1nm, a step size of 1nm, a time perpoint of 0.5s, and a heating range of 25～95℃, the heating rate is 3℃/min. CD spectra were collected every 5°C, and data analysis was performed with Origin 9.0 software. The test results are shown in Figure 1. As can be seen from Figure 1, compared with the control group (c-MYCpu22 nucleic acid solution alone), the thermal stability curve of the c-MYC G-quadruplex in the experimental group was significantly shifted to the right after the addition of the c-MYC transcription inhibitor m-Se3. The T _m shift value was 11.4°C; indicating that the m-Se3 compound was able to stabilize c-MYC G-quadruplex in vitro.

Take the c-MYC transcription inhibitor in Examples 1 to 8 of the present invention and prepare 100 μL of a solution with a working concentration of 1 μmol/L with G-quadruplex buffer, add it to a 3×3 mm quartz cuvette and place it in in the fluorescence spectrometer. Set the corresponding excitation wavelength and emission wavelength range of the c-MYC transcription inhibitor, the excitation and emission slits are 5 nm, and collect the fluorescence spectrum of the c-MYC transcription inhibitor solution. Add nucleic acid stock solution to c-MYC transcription inhibitor solution to a working concentration of 2 μmol/L. Make the concentration ratio of c-MYC transcription inhibitor and nucleic acid 1:2. After fully mixing and standing for 30s, the fluorescence spectra of c-MYC transcription inhibitor and nucleic acid solution were collected under the same conditions as above. The test results are shown in Figure 2. Among them, pu22(c-MYC), pu22mut, c-kit1, hras and htg22 are all G-quadruplex sequences; Figure 2(a) shows the effect of Se1 on c-MYC G-quadruplex; Figure 2(b) shows Se2 on c-MYC G-quadruplex The effect of quadruplex; Figure 2(c) is the effect of Se3 on c-MYC G-quadruplex; Figure 2(d) is the effect of m-Se1 on c-MYC G-quadruplex Figure; Figure 2(e) is the effect of m-Se2 on c-MYC G-quadruplex; Figure 2(f) is the effect of m-Se3 on c-MYC G-quadruplex; Figure 2 (g) is a graph showing the effect of p-Se1 on c-MYC G-quadruplex; Figure 2(h) is a graph showing the effect of m-p-Se1 on c-MYC G-quadruplex. It can be seen from Figure 2 that the c-MYC transcriptional inhibitors m-Se1 and m-Se3 have the strongest selectivity for c-MYC G-quadruplex.

(2) Inhibitory effect on the transcription and expression of HepG2 c-MYC gene in human hepatoma cells

In order to explore whether m-Se3 down-regulates c-MYC transcription, it also affects the expression levels of other oncogenes, we verified by RT-qPCR experiments. Three oncogenes VEGF, KRAS and c-KIT whose promoter regions can form G-quadruplex were selected. GAPDH was used as an internal reference, and the corresponding cDNA fragments were amplified by specific primers for each oncogene. HepG2 cells in logarithmic growth phase were seeded in 6-well plates at 200,000 cells per well, and cultured for 24h in a 37°C incubator containing 5% CO ₂ . Take m-Se3 and prepare it with a medium containing 10% fetal bovine serum to a working concentration of 2.5 μmol/L. The medium in the 6-well plate was discarded, and 2 mL of medium containing 2.5 μmol/L m-Se3 was added to each well, and the control group was 2 mL of compound-free medium. Placed in a 37°C incubator with 5% _CO2 for 48h. The medium was discarded, cells were washed with PBS, PBS was added, and cells were collected by centrifugation in an EP tube. PBS was aspirated, followed by RNA extraction. RNA samples were stored in a -80°C freezer. Then, the genomic DNA in the RNA sample was removed to reduce the interference of the genomic DNA on the quantitative analysis of the cDNA obtained by subsequent reverse transcription, and then stored in a 4° C. refrigerator to obtain a reaction solution. Then, according to the instructions of the reverse transcription kit, prepare the RT reaction solution, mix the RT reaction solution with the above reaction solution, react in the PCR instrument at 37 °C for 15 min, 85 °C for 5 s, and then cool to 4 °C for placement. Then add the cDNA and PCR system to the PCR plate, seal with the PCR sealing film, centrifuge and place it in the real-time fluorescence quantitative PCR instrument, and carry out forty cycles of 95°C for 30s, 95°C for 5s, 62°C for 1 min, and 40°C for 30s After amplification, the cells were placed at 4°C and the relative changes in RNA levels were calculated by Ct value. The calculation results are shown in Figure 3. The RT-PCR results in Figure 3 show that the m-Se3 in the present invention has a strong inhibitory effect on the transcription of the c-MYC gene, and has high selectivity. In conclusion, m-Se3 can selectively inhibit the transcription of c-MYC, and all of them have little effect on the transcription of other oncogenes.

(3) Inhibitory effect on the proliferation and migration of human hepatoma cells HepG2

HepG2 cells in logarithmic growth phase were seeded in 6-well plates at 500 cells per well, and cultured in a 37°C incubator with 5% CO ₂ for 24 h. Discard the medium of the 6-well plate, and add m-Se3 containing different concentrations to each well (concentrations are: 0 μmol/L, 0.125 μmol/L, 0.25 μmol/L, 0.5 μmol/L, 1 μmol/L, 2 μmol/L) 2 mL of medium. Place in a 37°C incubator with 5% _CO for 14 days, and change the medium every 3 days. The medium was discarded, and the cells were washed 3 times with 0.01 mol/L PBS buffer solution. Cells were fixed with 4% paraformaldehyde for 20 min, and the paraformaldehyde was discarded. Stain with 1% crystal violet solution for 15 min. The cells were washed with water to remove excess dye, air-dried, and photographed. The results are shown in Figure 4. Figure 4(a) shows the effect of m-Se3 on the proliferation inhibition of HepG2 cells when the concentration of m-Se3 is 0 μmol/L. Figure 4(b) ) is a graph of the inhibitory effect on the proliferation of HepG2 cells when the concentration of m-Se3 is 0.125 μmol/L; Fig. 4(c) is a graph of the inhibitory effect on the proliferation of HepG2 cells when the concentration of m-Se3 is 0.25 μmol/L; Fig. 4 (d) is a graph of the inhibitory effect on the proliferation of HepG2 cells when the concentration of m-Se3 is 0.5 μmol/L; Figure 4(e) is a graph of the inhibitory effect on the proliferation of HepG2 cells when the concentration of m-Se3 is 1 μmol/L; 4(f) is the graph of the inhibitory effect on the proliferation of HepG2 cells when the concentration of m-Se3 is 2 μmol/L. It can be seen from Figure 4 that with the increase of m-Se3 concentration, m-Se3 significantly inhibited the colony formation of HepG2 cells in a dose-dependent manner, and high concentration of m-Se3 had a stronger inhibitory effect on the colony of HepG2 cells.

HepG2 cells in logarithmic growth phase were seeded in 6-well plates at 500,000 cells per well, and cultured in a 37°C incubator containing 5% CO ₂ for 24 hours. Aspirate the medium. Use a micropipette tip to draw a line of equal width in the center of the monolayer. The scratches were washed with sterile 0.01mol/L PBS buffer solution to remove cells on the scratches. Observe and take pictures under the microscope to record the scratches of the cell migration 0h, as shown in Figure 5(a) to Figure 5(f). Micrograph of cell migration at 0 h. Then, 2 mL of concentration gradient m-Se3 compound working solution (concentrations: 0 μmol/L, 0.3 μmol/L, 0.6 μmol/L, 1.2 μmol/L, 2.5 μmol/L, 5 μmol/L) were added. Placed in a 37°C incubator with 5% _CO2 for 48h. Observe and photograph under the microscope to record the scratches of the cells migrated for 48h. The results are shown in Figures 5(g) to 5(l), in which Figure 5(g) shows the inhibitory effect of m-Se3 on the migration of HepG2 cells for 48h when the concentration of m-Se3 is 0 μmol/L; Figure 5(h) shows Figure 5(i) shows the inhibitory effect of m-Se3 on the migration of HepG2 cells for 48 hours when the concentration of m-Se3 is 0.3μmol/L; Figure 5 (j) is the inhibitory effect of m-Se3 on the migration of HepG2 cells for 48 hours when the concentration of m-Se3 is 1.2 μmol/L; Figure 5(k) is the inhibitory effect of m-Se3 on the migration of HepG2 cells for 48 hours when the concentration of m-Se3 is 2.5 μmol/L Fig. 5(l) is a graph showing the inhibitory effect of m-Se3 on the migration of HepG2 cells for 48h when the concentration of m-Se3 is 5μmol/L. It can be seen from Figure 5 that after 48 hours of culture, the intercellular space in the non-administration group was significantly reduced, and migration occurred. However, with the increase of m-Se3 concentration, the shrinkage of the intercellular space is significantly reduced, the scratches are obvious, and the cell migration is reduced, indicating that the m-Se3 in the present invention can significantly inhibit the migration of HepG2 cells.

(4) m-Se3 inhibits the growth of human hepatoma cells in vivo

HepG2 cells in logarithmic growth phase were collected, and 1×10 ⁸ cells/100 μL of cell suspension was subcutaneously injected into 4-5 week-old BALB/c-nu/nu male mice (immuno-deficient mice, which did not have thymus) underarm. After the tumor volume grew more than 50 mm, the mice were randomly divided into ³ groups, with 5 mice in each group. Among the 3 groups, one administration group, one solvent group and one control group were set. Among them, the administration group was given m-Se3 drug, The administration dose was 15 mg/kg; the solvent group was given the same amount of normal saline solution, and the control group was given the chemotherapy drug Doxorubicin (1 mg/kg). The mice were administered once every two days, and the weight and tumor volume of the mice were measured and recorded. After 28 days of administration, the mice were killed by dislocation. The graph of m-Se3 inhibiting the growth of hepatoma cells HepG2 in vivo is shown in Figure 6; the weight test of mice The results are shown in Figure 7. It can be seen from Figure 6 and Figure 7 that compared with the solvent group, the average tumor volume of the administration group was significantly reduced. It can be seen that m-Se3 can significantly inhibit the growth of the tumor without causing the weight loss of the mice.

(5) Cancer cell inhibitory activity

The logarithmic growth phase of human hepatoma cells HepG2, human colon cancer cells HCT116, human colon adenocarcinoma cells RKO, a total of three cancer cell lines and a human normal colon epithelial cell NCM460 were used to inoculate 3000 cells per well in 96-well plates. Placed in a 37°C incubator with 5% _CO2 for 24h. The c-MYC transcription inhibitor in Examples 1 to 8 of the present invention was prepared with a medium containing 10% fetal bovine serum to prepare 0 μmol/L, 3.125 μmol/L, 6.25 μmol/L, 12.5 μmol/L, 25 μmol/L, respectively. L, 50 μmol/L, 100 μmol/L working concentration. The medium in the 96-well plate was discarded, and 100 μL of the medium containing the above compounds with different concentrations was added to each well, and three replicate wells were set for each concentration. Placed in a 37°C incubator with 5% _CO2 for 48h. Take MTT solution (3-(4,5-dimethylthiazole-2)-2,5-diphenyltetrazolium bromide, thiazole blue), mix it with serum-free medium in a ratio of 2:8 . Discard the medium of the 96-well plate, add 100 μL of MTT-containing medium to each well, and incubate for 4 h in a 37°C incubator with 5% CO ₂ . Discard the mixed solution of MTT and medium, add 100 μL of DMSO to each well, and mix gently. The absorbance values of each well at wavelengths of 570 nm and 490 nm were detected by a microplate reader. The _IC50 values of the c-MYC transcription inhibitor for different cells were calculated, and the results are shown in Table 1.

Table 1 IC ₅₀ values of c-MYC transcription inhibitors in Examples 1 to 8 of the present invention on different cells

It can be seen from Table 1 that the cancer cell inhibitory activity of c-MYC transcriptional inhibitors is significantly correlated with the binding ability and selectivity of its c-MYC G-quadruplex. The c-MYC transcription inhibitor of the present invention has obvious proliferation inhibition toxicity to cancer cells, and the reason may be the result of enhanced binding to c-MYC G-quadruplex. Taken together, the compounds that performed better in the inhibition of cancer cell proliferation were m-Se1, m-Se3 and m-p-Se1, which were combined in the specific binding of c-MYC G-quadruplex and the inhibition of cancer cell proliferation. Two benzoselenoazoles with better performance are m-Se1 and m-Se3, respectively.

The embodiments of the present invention have been described in detail above, but the present invention is not limited to the above-mentioned embodiments, and various changes can be made within the scope of knowledge possessed by those of ordinary skill in the art without departing from the spirit of the present invention. Furthermore, the embodiments of the present invention and features in the embodiments may be combined with each other without conflict.

Claims (10)

1. a c-MYC transcription inhibitor is characterized in that: comprise the compound shown in any one of formula (I)～(IV) or its pharmaceutically acceptable salt, isomer, solvate;

Wherein, A ^- is N methylation anion, iodide, bromide, p-toluenesulfonate, trifluoroacetate, perchlorate, tetrafluoroborate, methylsulfate or trifluoromethanesulfonate; R1 and R2 are independently selected from fluorine, chlorine, bromine, hydrogen, amino or amine substituents; _R3 is independently selected from an aromatic ring, a substituted aromatic ring, or an aromatic heterocyclic ring. 2. c-MYC transcription inhibitor according to claim 1, is characterized in that: in formula (I)～(IV): A ^- is iodide, bromide, p-toluenesulfonate, trifluoroacetate, perchlorate, tetrafluoroborate, methyl sulfate or trifluoromethanesulfonate; R1 and R2 are independently selected from fluorine, hydrogen, amino or amine substituents; _R3 is independently selected from an aromatic ring, a substituted aromatic ring, or an aromatic heterocyclic ring. 3. c-MYC transcription inhibitor according to claim 2, is characterized in that: in formula (I)～(IV): A ^- is iodide, bromide, p-toluenesulfonate, trifluoroacetate, perchlorate, tetrafluoroborate, methyl sulfate or trifluoromethanesulfonate; R1 and R2 are independently selected from fluorine, hydrogen, amino or amine substituents; _R3 is independently selected from

4. c-MYC transcription inhibitor according to claim 3, is characterized in that: in formula (I)～(IV): A ^- is iodide ion; Both R1 and R2 are hydrogen; _R3 is independently selected from

5. The preparation method of the c-MYC transcription inhibitor according to any one of claims 1 to 4, characterized in that: comprising the following steps: by

As the raw material, the compound represented by the formula (I) or the compound represented by the formula (II) is synthesized; with

For the raw material to synthesize the compound shown in formula (III) or the compound shown in formula (IV); The preparation method of the compound shown in the formula (I), comprises the following steps: Will

Mixed reaction with selenium and cuprous bromide to obtain

followed by

react with hypophosphorous acid

Then react with acetylacetone to obtain

followed by

and

reaction to obtain the compound represented by the formula (I); or, The preparation method of the compound shown in the formula (III), comprises the following steps: Will

Mixed reaction with selenium and cuprous bromide to obtain

followed by

Reaction with tributylphosphine and acetic acid to obtain

followed by

and

reaction to obtain the compound represented by the formula (III); or, The preparation method of the compound shown in the formula (II) or the compound shown in the formula (IV) comprises the following steps: Will

react with methylating reagents to obtain

followed by

and

reaction to obtain the compound represented by the formula (II) or the compound represented by the formula (IV); Or, react the compound shown in formula (I) or the compound shown in formula (III) with a methylating reagent to obtain the compound shown in formula (II) or compound shown in formula (IV); wherein A ^- , R1, R2, and _R3 are as defined in any one of claims 1 to 4. 6. A G-quadruplex ligand, characterized in that it comprises at least one of the compounds represented by formulae (I) to (IV);

wherein A ^- , R1, R2, and _R3 are as defined in any one of claims 1 to 4. 7 . An antitumor drug, characterized in that it comprises the c-MYC transcription inhibitor according to any one of claims 1 to 4 . 8. The antitumor drug according to claim 7, wherein the tumor comprises liver cancer, colon cancer or colon adenocarcinoma. 9 . The anti-tumor drug according to claim 7 , wherein the content of the c-MYC transcription inhibitor in the anti-tumor drug is 0.05-50 wt %. 10 . 10. Use of the c-MYC transcription inhibitor according to any one of claims 1 to 4 in the preparation of a medicament for preventing or treating tumors.

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