A class of scutellarein derivatives and their use in medicine

Abstract

The application discloses a scutellarein derivative and application thereof in medicine. The compound of formula I or pharmaceutically acceptable salt thereof is an effective IGF2BP2 small molecule inhibitor, has obvious inhibitory activity on IGF2BP2, inhibits RNA reader at the proteinase level, and modifies and regulates m 6 A level, and can be used for treating diseases related to IGF2BP2, such as breast cancer, colorectal cancer, pancreatic cancer, hepatocellular carcinoma, acute myeloid leukemia, T-cell acute lymphoblastic leukemia, nasopharyngeal carcinoma and various tumors.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical chemistry, and particularly relates to a scutellarein derivative and the use thereof in medicine. BACKGROUND

[0002] N 6 - methyladenosine (m 6 A) is the most abundant modification in eukaryotic RNA, which is a dynamic and reversible RNA modification including writers, erasers and readers. m 6 A modification plays a role in promoting or hindering in cell cycle regulation, cell differentiation, cell state change, stress response, etc. More and more studies have found that m 6 A modification plays an increasingly important role in the occurrence and development of tumors and cancers, and has the potential to become a biomarker of cancer. Human insulin-like growth factor 2 (IGF2) mRNA binding protein 2 (IGF2BP2) is a RNA binding protein that regulates various biological processes. In recent years, studies have found that IGF2BP2 plays many roles in various biological processes, especially in tumors, and have speculated on the mechanism of its anti-cancer activity. In addition, targeting IGF2BP2 or its downstream mechanism as an effective treatment for different types of tumors has also received extensive attention.

[0003] IGF2BP2 plays an important role in breast cancer, colorectal cancer, pancreatic cancer, hepatocellular carcinoma, acute myeloid leukemia, T-cell acute lymphoblastic leukemia, nasopharyngeal carcinoma and many other tumors. Therefore, using small molecule inhibitors to inhibit the enzymatic activity of IGF2BP2 can be used to treat indications related to the dysfunction of IGF2BP2 protein function.

[0004] Currently, there is no report on high-activity IGF2BP2 small molecule inhibitors. SUMMARY

[0005] The purpose of the present application is to overcome the above-mentioned deficiencies in the prior art, and to provide a scutellarein derivative.

[0006] Another purpose of the present application is to provide a preparation method of the scutellarein derivative.

[0007] Still another purpose of the present application is to provide the use of the scutellarein derivative.

[0008] A scutellarein derivative or a pharmaceutically acceptable salt thereof as shown in the general formula (I):

[0009]

[0010] R is mono- or polysubstituted hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, nitro, halogen, cyano, aldehyde, hydroxy, amino, substituted amino, the substituents being C1-C4 alkyl, allyl, methyl, trifluoromethyl or difluoromethyl.

[0011] As a preferred embodiment of the present application, R is selected from mono- or polysubstituted H, methyl, halogen, hydroxy, amino.

[0012] The compounds of the general formula I according to the present application can also exist in the form of their salts, which are converted in the body into the compounds of the formula I. For example, within the scope of the present application, the compounds according to the present application are converted into the form of pharmaceutically acceptable salts according to processes known in the art and used as salts.

[0013] A scutellarein derivative or a pharmaceutically acceptable salt thereof, characterized by being any one compound selected from the following or a pharmaceutically acceptable salt thereof:

[0014]

[0015]

[0016] A preparation method of a scutellarein derivative according to the present application, comprising the following steps:

[0017] (1) adding acetone, water, potassium ferricyanide and hydrogen peroxide to 1,3,5-trimethoxybenzene, stirring at room temperature, and obtaining compound 2 through an oxidation reaction;

[0018] (2) adding sodium hyposulfite and water to compound 2, and obtaining compound 3 through heating at 100°C;

[0019] (3) adding dichloromethane, acetic anhydride and boron trifluoride ether to compound 3, refluxing and heating, and obtaining compound 4 through a Friedel-Crafts acylation reaction;

[0020] (4) adding methanol, proline, triethylamine and 3-fluoro-4-methoxybenzaldehyde to compound 4, stirring at room temperature, and obtaining compound 6 through a Michael addition reaction;

[0021] (5) adding DMSO and iodine to compound 6, stirring and heating, and obtaining compound 7 through ring closure;

[0022] (6) adding dichloromethane and boron tribromide to compound 7, and obtaining compound 8 through reaction from ice bath to room temperature;

[0023] (7) adding acetic anhydride and sodium acetate to compound 8, and obtaining compound 9 through heating reaction;

[0024] (8) To compound 9, add acetonitrile, bromosugar, potassium carbonate, and heat to react to obtain compound 11;

[0025] (9) To compound 11, add acetone, sodium hydroxide, and ice bath to react to obtain compound 12.

[0026] The reaction route of the above steps (1) to (9) and the structures of compounds (1) to (12) are as follows:

[0027]

[0028] The application of the scutellarein derivative or the pharmaceutically acceptable salt thereof in the preparation of an IGF2BP2 inhibitor.

[0029] The compound of formula I or the pharmaceutically acceptable salt thereof is used for preparing a drug for treating a disease related to the dysfunction of IGF2BP2 protein. The disease related to the dysfunction of IGF2BP2 protein is breast cancer, colorectal cancer, pancreatic cancer, hepatocellular carcinoma, acute myeloid leukemia, T-cell acute lymphoblastic leukemia, nasopharyngeal carcinoma and the like.

[0030] A pharmaceutical composition, wherein the active ingredient of the pharmaceutical composition comprises the scutellarein derivative or the pharmaceutically acceptable salt thereof, the prodrug thereof or the hydrate or solvate thereof.

[0031] As a preferred embodiment of the application, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0032] Beneficial effects: The compound of formula I or the pharmaceutically acceptable salt thereof provided by the application is an effective IGF2BP2 small molecule inhibitor, has obvious inhibitory activity on IGF2BP2, inhibits RNA reader at the level of protease, modifies the regulation of m 6 A level, and can be used for treating diseases related to IGF2BP2, such as breast cancer, colorectal cancer, pancreatic cancer, hepatocellular carcinoma, acute myeloid leukemia, T-cell acute lymphoblastic leukemia, nasopharyngeal carcinoma and the like. DETAILED DESCRIPTION

[0033] The preferred embodiments of the application will be described in detail below with reference to the examples. It should be understood that the following examples are given only for the purpose of illustration and are not intended to limit the scope of the application. Those skilled in the art can make various modifications and replacements to the application without departing from the spirit and principles of the application.

[0034] In the following examples, the experimental methods used are conventional methods unless otherwise specified.

[0035] The materials, reagents, etc. used in the following examples, unless otherwise specified, can be obtained commercially.

[0036] Example 1

[0037]

[0038] Step 1: Synthesis of compound 2

[0039] Compound 1 (20.00 g, 118.91 mmol) was dissolved in 100 ml of acetone, 10 ml of water was added, potassium cyanide (2.35 g, 7.13 mmol) was added, and finally 30% hydrogen peroxide (41.46 g, 1.22 mmol) was added. Stirring was carried out at room temperature for 10 h, and TLC monitoring showed that the reaction of raw material 1 was complete. 100 ml of water was added, and stirring was continued for 30 min. Filtration was carried out, and the filter cake was washed with water until yellow. After drying, the next step was carried out directly. The yield was 99.50%. 1 H NMR (300 MHz, DMSO-d6) δ: 7.22 (s, 2H), 3.72 (s, 6H).

[0040] Step 2: Synthesis of compound 3

[0041] To compound 2 (19.90 g, 118.35 mmol), 200 ml of water was added, and then sodium dithionite (30.91 g, 177.52 mmol) was added. Heating was carried out at 100°C for 2 h, and TLC monitoring showed that the reaction of raw material 2 was complete. Cooling to room temperature resulted in the precipitation of a large amount of white solid. Filtration was carried out, and drying was carried out directly. The next step was carried out directly.

[0042] Step 3: Synthesis of compound 4

[0043] To compound 3 (11.3 g, 66.41 mmol), 100 ml of dichloromethane was added, followed by acetic anhydride (54 g, 528.95 mmol) and boron trifluoride ether (33 g, 232.51 mmol). Heating was carried out under reflux for 8 h, and TLC monitoring showed that the reaction of raw material 3 was complete. After cooling to room temperature, suction filtration was carried out, and drying was carried out to obtain 18.20 g of yellow solid, with a yield of 90.73%. Without purification, the next step was carried out directly.

[0044] Step 4: Synthesis of compound 6

[0045] To compound 4, 100 ml of methanol was added, followed by compound 5 (12.31 g, 90.39 mmol), proline (6.94 g, 60.26 mmol), and triethylamine (12.20 g, 120.52 mmol). Stirring was carried out at room temperature for 8 h, and TLC monitoring showed that the reaction of raw material 4 was complete. Cooling to room temperature was carried out, 100 ml of water was added, and stirring was carried out. Suction filtration was carried out, and the filter cake was recrystallized with ethanol to obtain 19.70 g of yellow solid, with a yield of 87.79%.1 H NMR (300 MHz, DMSO-d6) δ: 7.69 (d, J = 8.5 Hz, 2H), 7.61 (d, J = 15.7 Hz, 1H), 7.39 (d, J = 15.7 Hz, 1H), 7.01 (d, J = 8.4 Hz, 2H), 6.46 (s, 1H), 3.81 (d, J = 2.7 Hz, 6H), 3.72 (s, 3H), 2.30 (s, 3H).

[0046] Step 5: Synthesis of compound 7

[0047] To compound 6, add 50 ml dimethyl sulfoxide, iodine (4.03 g, 15.87 mmol), heat the reaction at 110 °C for 8 h, TLC monitor the complete reaction of starting material 6, after cooling to room temperature, add saturated aqueous sodium sulfite 50 ml, continue stirring for 30 min, suction filtration, oven dry, column chromatography separation (eluent: petroleum ether / ethyl acetate = 4:1), to obtain white solid 17.04 g, yield 87%. 1 H NMR (300 MHz, DMSO-d6) δ: 8.09 - 8.00 (m, 2H), 7.32 (s, 1H), 7.16 - 7.08 (m, 2H), 6.77 (s, 1H), 3.94 (s, 3H), 3.86 (s, 3H), 3.77 (s, 3H), 2.34 (s, 3H).

[0048] Step 6: Synthesis of compound 8

[0049] To compound 7, add 50 ml dichloromethane, add 10 ml boron tribromide under ice bath, after the system is stable, move to room temperature and stir for 6 h, TLC monitor the complete reaction of starting material 7, quench the reaction by adding methanol under ice bath, filter, recrystallize the filter cake with methanol to obtain yellow solid 11.40 g, yield 86.56%. 1 H NMR (300 MHz, DMSO-d6) δ: 12.84 (s, 1H), 10.51 (s, 1H), 10.35 (s, 1H), 8.80 (s, 1H), 7.96 (d, J = 8.7 Hz, 2H), 6.96 (d, J = 8.5 Hz, 2H), 6.79 (s, 1H), 6.62 (s, 1H).

[0050] Step 7: Synthesis of compound 9

[0051] To compound 8, add 50 ml acetic anhydride, sodium acetate (16.34 g, 199.13 mmol), heat and stir at 80 °C for 8 h, TLC monitor the complete reaction of starting material 8, cool to room temperature, add water, filter, recrystallize the filter cake with ethyl acetate / methanol to obtain white solid 17.9 g, yield 98.90%. 1H NMR (300 MHz, DMSO-d6) δ: 8.29 - 8.20 (m, 2H), 7.94 (s, 1H), 7.50 - 7.43 (m, 2H), 7.05 (s, 1H), 2.48 - 2.43 (m, 9H), 2.41 (s, 3H).

[0052] Step 8: Synthesis of compound 11

[0053] To compound 9, add 50 ml of acetonitrile, tetrabutylammonium bromide (15.24 g, 47.27 mmol), bromosugar (31.29 g, 78.79 mmol), potassium carbonate (16.33 g, 118.18 mmol), heat the reaction at 40 °C for 8 h, monitor the reaction completion by TLC, filter off the potassium carbonate, remove the solvent under reduced pressure, dissolve in ethyl acetate, wash with water 2-3 times, dry the organic phase over anhydrous sodium sulfate, and distill under reduced pressure to obtain a brown solid, recrystallize with ethanol to obtain a white solid 20.20 g, yield 70.38%. No further purification is required to proceed to the next step.

[0054] Step 9: Synthesis of compound C-1

[0055] To compound 11, add 55 ml of acetone, add 50 ml of 3M NaOH aqueous solution under ice bath, react for 2 h under ice bath, monitor the reaction completion by TLC, adjust the pH to 3-4 with 3M HC1, continue stirring for 30 min, a yellow solid precipitates, filter, recrystallize the filter cake with methanol to obtain a yellow solid 6.32 g, yield 49.30%. 1 H NMR (500 MHz, Chloroform-d) δ 8.17 (s, 1H), 7.70 (dd, J = 9.8, 1.9 Hz, 1H), 7.59 (dd, J = 8.0, 1.9 Hz, 1H), 6.99 - 6.92 (m, 2H), 6.63 (d, J = 15.2 Hz, 2H), 5.21 (d, J = 5.9 Hz, 1H), 5.08 - 5.02 (m, 1H), 4.93 - 4.86 (m, 1H), 4.58 - 4.50 (m, 1H), 3.93 - 3.87 (m, 1H), 3.52 (dtt, J = 6.7, 3.0, 1.3 Hz, 2H), 3.52 - 3.44 (m, 1H).

[0056] Example 2

[0057]

[0058] Synthesized according to the preparation method of Reference Example 1. Compound C-2 was obtained as a yellow solid. The yield was 70.98%. 1HNMR (300 MHz, Chloroform-d) δ 8.29 - 8.23 (m, 2H), 8.17 (s, 1H), 7.46 - 7.38 (m, 2H), 6.97 (s, 1H), 6.59 (s, 1H), 5.21 (d, J = 5.8 Hz, 1H), 5.09 - 5.02 (m, 1H), 4.93 - 4.86 (m, 1H), 4.58 - 4.50 (m, 1H), 3.93 - 3.87 (m, 1H), 3.52 (dddd, J = 9.0, 4.6, 2.6, 1.2 Hz, 2H), 3.52 - 3.44 (m, 1H).

[0059] Example 3

[0060]

[0061] The synthesis was performed according to the procedure described in Reference Example 1. Compound C-3 was obtained as a yellow solid. The yield was 69.81%. 1 HNMR (300 MHz, Chloroform-d) δ 8.29 - 8.23 (m, 2H), 8.17 (s, 1H), 7.46 - 7.38 (m, 2H), 6.97 (s, 1H), 6.59 (s, 1H), 5.21 (d, J = 5.8 Hz, 1H), 5.09 - 5.02 (m, 1H), 4.93 - 4.86 (m, 1H), 4.58 - 4.50 (m, 1H), 3.93 - 3.87 (m, 1H), 3.52 (dddd, J = 9.0, 4.6, 2.6, 1.2 Hz, 2H), 3.52 - 3.44 (m, 1H).

[0062] Example 4

[0063]

[0064] The synthesis was performed according to the procedure described in Reference Example 1. Compound C-4 was obtained as a yellow solid. The yield was 71.84%. 1 HNMR (300 MHz, Chloroform-d) δ 8.29 - 8.23 (m, 2H), 8.17 (s, 1H), 7.46 - 7.38 (m, 2H), 6.97 (s, 1H), 6.59 (s, 1H), 5.21 (d, J = 5.8 Hz, 1H), 5.09 - 5.02 (m, 1H), 4.93 - 4.86 (m, 1H), 4.58 - 4.50 (m, 1H), 3.93 - 3.87 (m, 1H), 3.52 (dddd, J = 9.0, 4.6, 2.6, 1.2 Hz, 2H), 3.52 - 3.44 (m, 1H).

[0065] Example 5

[0066]

[0067] The preparation method described in Example 1 was followed for synthesis. Compound C-5 was obtained as a yellow solid. The yield was 75.44%. 1 HNMR(500MHz,Chloroform-d)δ8.17(s,1H),7.88–7.82(m,2H),7.63–7.57(m,2H),6.97(s,1H),6.59(s,1H),5.21(d,J=5.8Hz,1H),5.08– 5.02(m,1H),4.93–4.86(m,1H),4.58–4.50(m,1H),3.93–3.87(m,1H),3.57–3.50(m,1H),3.51(dt,J=2.9,1.5Hz,1H),3.52–3.44(m,1H).

[0068] Example 6

[0069]

[0070] The preparation method described in Example 1 was followed for synthesis. Compound C-6 was obtained as a yellow solid. The yield was 72.98%. 1 HNMR(500MHz,Chloroform-d)δ8.17(s,1H),7.75–7.69(m,2H),7.27–7.22(m,2H),6.97(s,1H),6.58(s,1H),5.21(d,J=5.8Hz,1H),5.08–5.02(m,1H) ,4.93–4.86(m,1H),4.58–4.50(m,1H),3.90(dt,J=8.7,2.5Hz,1H),3.52(d ddd,J=6.8,4.6,2.8,1.3Hz,2H),3.52–3.44(m,1H),2.39(d,J=1.8Hz,1H).

[0071] Example 7

[0072]

[0073] The preparation method described in Example 1 was followed for synthesis. Compound C-7 was obtained as a yellow solid. The yield was 73.87%. 1HNMR (500 MHz, Chloroform-d) δ 8.17 (s, 2H), 7.88 (ddd, J = 9.1, 5.0, 1.9 Hz, 2H), 7.71 (ddd, J = 8.1, 5.0, 1.9 Hz, 2H), 7.27 (ddd, J = 9.2, 8.0, 5.0 Hz, 2H), 6.97 (s, 2H), 6.62 (s, 2H), 5.21 (d, J = 5.8 Hz, 2H), 5.08 - 5.02 (m, 2H), 4.93 - 4.86 (m, 2H), 4.58 - 4.50 (m, 2H), 3.93 - 3.87 (m, 2H), 3.52 (dddd, J = 9.0, 4.6, 2.6, 1.3 Hz, 4H), 3.52 - 3.47 (m, 1H), 3.49 - 3.44 (m, 1H).

[0074] Example 8

[0075]

[0076] The synthesis was performed according to the procedure of Reference Example 1. Compound C-8 was obtained as a yellow solid. Yield 81.23%. 1 HNMR (500 MHz, Chloroform-d) δ 8.17 (s, 2H), 7.88 (ddd, J = 9.1, 5.0, 1.9 Hz, 2H), 7.71 (ddd, J = 8.1, 5.0, 1.9 Hz, 2H), 7.27 (ddd, J = 9.2, 8.0, 5.0 Hz, 2H), 6.97 (s, 2H), 6.62 (s, 2H), 5.21 (d, J = 5.8 Hz, 2H), 5.08 - 5.02 (m, 2H), 4.93 - 4.86 (m, 2H), 4.58 - 4.50 (m, 2H), 3.93 - 3.87 (m, 2H), 3.52 (dddd, J = 9.0, 4.6, 2.6, 1.3 Hz, 4H), 3.52 - 3.47 (m, 1H), 3.49 - 3.44 (m, 1H).

[0077] Example 9

[0078]

[0079] The synthesis was carried out by following the procedure of Reference Example 1. Compound C-9 was obtained as a yellow solid. Yield 86.33 %.1H NMR (500 MHz, Chloroform-d) δ 8.17 (s, 2H), 7.66 (s, 2H), 7.41 - 7.36 (m, 4H), 6.97 (s, 2H), 6.64 (s, 2H), 5.21 (d, J = 5.8 Hz, 2H), 5.08 - 5.02 (m, 2H), 4.93 - 4.86 (m, 2H), 4.58 - 4.50 (m, 2H), 3.93 - 3.87 (m, 2H), 3.56 - 3.50 (m, 2H), 3.51 (dt, J = 3.1, 1.5 Hz, 2H), 3.52 - 3.47 (m, 1H), 3.49 - 3.44 (m, 1H).

[0080] Example 10

[0081]

[0082] The synthesis was carried out by following the procedure of Reference Example 1. Compound C-10 was obtained as a yellow solid. Yield 88.11 %. 1 1H NMR (500 MHz, Chloroform-d) δ 8.17 (s, 1H), 7.97 - 7.91 (m, 2H), 7.58 - 7.51 (m, 1H), 7.54 - 7.47 (m, 2H), 6.97 (s, 1H), 6.58 (s, 1H), 5.23 - 5.19 (m, 1H), 5.09 - 5.02 (m, 1H), 4.94 - 4.86 (m, 1H), 4.57 - 4.50 (m, 1H), 3.93 - 3.86 (m, 1H), 3.51 (dddd, J = 8.5, 3.9, 2.4, 1.4 Hz, 2H), 3.51 - 3.44 (m, 1H).

[0083] Example 11, Expression and purification of IGF2BP2 protein

[0084] IGF2BP2 gene plasmid was purchased from GeneScript Corporation

[0085] Experimental procedure:

[0086] The E. coli BL21 (DE3) strain was transfected with the recombinant plasmid, and the bacteria were recovered in sterile LB medium at 37°C. A single colony was picked and transferred to 10 mL of LB liquid medium (containing 50 μg / mL kanamycin, Amp) and incubated at 37°C (220 rpm) overnight. The bacteria were then transferred to 1 L of LB liquid medium (containing 50 μg / mL kanamycin, Amp) and incubated at 37°C (220 rpm) for 6-8 hours until the OD600 was 0.6-0.8. The temperature was then reduced to 12°C, and 1 mM IPTG (Merck) was added to induce expression for 16 hours (180 rpm). The bacteria were then collected and stored at -80°C for later use.

[0087] 4 g of the bacteria from the previous step were added to 40 mL of a bacteria lysis solution, mixed, and then PMSF (Biyun Tian) was added. The mixture was ultrasonically lysed for 40 minutes, and the lysed mixture was subjected to low-temperature high-speed centrifugation (10000 rpm, 20 min, 4°C). The supernatant was filtered (0.4 μm microporous filter), and the AKTA pure25 (GE Healthcare, Life Sciences) was used to separate and purify the protein using a His column (equilibration solution: 20 mM pH 8.0 Tris-HCl, 300 mM NaCl, 10 mM imidazole; elution solution: 20 mM pH 8.0 Tris-HCl, 300 mM NaCl, 500 mM imidazole). The molecular weight and purity of the protein were confirmed by 10% SDS-PAGE, and the protein was dialyzed overnight (20 mM pH 8.0 Tris-HCl, 300 mM NaCl). The concentration of the obtained protein was determined by BCA, and the protein was stored at -80°C for later use.

[0088] 2. The fluorescence polarization (FP) assay was used to determine the inhibitory activity of the compound on IGF2BP2.

[0089] The present application is based on a fluorescent molecular probe that binds to IGF2BP2, which is used to study scutellarin competition with IGF2BP2 and m 6 A method for determining the inhibition rate of scutellarin at different concentrations, and then calculating the IC 50 value.

[0090] The equipment and reagents used are as follows:

[0091] The instrument used in this experiment was a SpectraMax Paradigm Multi-Mode Microplate Reader (Molecular Devices). The protein used was IGF2BP2 (a protein expressed and purified in our laboratory, with the sequence: EQEIVNLFIPTQAVG AIIGKKGAHI KQLARFAGAS IKIAPAEGPD VSERMVIITG PPEAQFKAQG RIFGKLKEENFFNPKEEVKL EAHIRVPSST AGRVIGKGGK TVNELQNLTS AEVIVPRDQT PDENEEVIVR IIGHFFASQTAQRKIREIVQ QVKQQE). The probe used was a fluorescently labeled m 6 All A-ssRNA (sequence) test compounds were prepared as 10 mM stock solutions in DMSO. The 384-well blackboard used in the experiment was manufactured by Corning.

[0092] Experimental steps:

[0093] The final test volume was 60 μL. The following solutions were added to each well in the following order: 20 μL of different concentrations of *Erigeron breviscapus* derivative (using a two-fold serial dilution of 10-14 times, initial concentration 100 μM), 20 μL of IGF2BP2 protein (300 nM, final concentration 100 nM), and 20 μL of fluorescent probe (300 nM, final concentration 10 nM). A blank control (40 μL pH = 7.5 Tris-HCl buffer + 20 μL 10 nM fluorescent probe) and a negative control (20 μL pH = 7.5 Tris-HCl buffer + 20 μL IGF2BP2 protein + 20 μL 10 nM fluorescent probe) were also included in each experiment. After adding the sample, the 384-well plate was covered with aluminum foil and incubated on a shaker at room temperature for 1 hour. Fluorescence was read using a SpectraMax Paradigm Multi-Mode Microplate Reader at an excitation wavelength of 485 nm and an emission wavelength of 535 nm. The mP value was calculated, and the inhibition rate was calculated using the following formula. Finally, the IC50 was calculated using GraphPad Prism 5.0. 50 value.

[0094] Inhibition rate = (mP value of the scutellarin derivative group - mP value of the blank group) / (mP value of the negative control group - mP value of the blank group) × 100%

[0095] The experimental results are shown in Table 1. Using unlabeled m 6 A-ssRNA was used as a positive control to test the IC50 of the scutellarin derivative against IGF2BP2 protein.50 Values.

[0096] Table 1 IC50 values of the compounds of the present application against IGF2BP2 protein 50 Values

[0097] Compound name IGF2BP2 inhibitory activity IC 50 (μM) C-1 1.21 C-2 2.22 C-3 2.52 C-4 4.61 C-5 10.28 C-6 12.84 C-7 2.22 C-8 4.77 C-9 0.512 C-10 10.85

[0098] From the results of the above table, the scutellarein derivatives of the present application have obvious inhibitory activity against IGF2BP2 and can be used as IGF2BP2 protein small molecule inhibitors to inhibit the binding of IGF2BP2 and mRNA.

[0099] In summary, the scutellarein derivatives of the present application have obvious inhibitory activity against IGF2BP2 and are effective IGF2BP2 inhibitors. Therefore, the scutellarein derivatives can be used for preparing drugs for treating clinical conditions related to IGF2BP2.

[0100] As described above, although the present application is described with reference to specific preferred embodiments and indicated and expressed, it is not to be construed as a limitation on the present application itself. Various changes can be made in form and details without departing from the spirit and scope of the present application defined by the appended claims.

Claims

1. A derivative of scutellarin as shown in general formula (I) or a pharmaceutically acceptable salt thereof: ， R can be monosubstituted or polysubstituted, and R is selected from hydrogen, halogen, hydroxyl, and C1-C6 alkyl. The scutellaria baicalensis derivative shown in general formula (I) is not a... and .

2. The scutellarin derivative or its pharmaceutically acceptable salt according to claim 1, characterized in that, R can be monosubstituted or polysubstituted, and R is selected from H, methyl, halogen, and hydroxyl.

3. A derivative of scutellarin B or a pharmaceutically acceptable salt thereof, characterized in that, Selected from any of the following compounds or their pharmaceutically acceptable salts: 、 、 、 、 、 、 、 。 4. A method for preparing the scutellaria baicalensis derivative as described in claim 1, characterized in that, Includes the following steps: (1) Add acetone, water, potassium ferricyanide and hydrogen peroxide to 1,3,5-trimethoxybenzene, stir at room temperature, and obtain compound 2 by oxidation reaction; (2) Sodium dithionite and water were added to compound 2 and heated at 100°C to obtain compound 3; (3) Add dichloromethane, acetic anhydride, and boron trifluoride diethyl ether to compound 3, heat under reflux, and obtain compound 4 by Friedel-Crafts acylation reaction; (4) Add methanol, proline, triethylamine and 3-fluoro-4-methoxybenzaldehyde to compound 4, stir at room temperature, and obtain compound 6 by Michael addition reaction; (5) Add DMSO and iodine to compound 6, heat and stir, and cyclize to obtain compound 7; (6) Add dichloromethane and boron tribromide to compound 7, and react in an ice bath at room temperature to obtain compound 8; (7) Add acetic anhydride and sodium acetate to compound 8 and heat to react to obtain compound 9; (8) Add acetonitrile, bromosulin, and potassium carbonate to compound 9 and heat to react and obtain compound 11; (9) Add acetone and sodium hydroxide to compound 11 and react in an ice bath to obtain compound 12 as shown; The reaction routes of steps (1) to (9) above and the structures of compounds (1) to (12) are as follows: 。 5. The use of any one of the scutellarin derivatives or pharmaceutically acceptable salts thereof according to claims 1-3 in the preparation of IGF2BP2 inhibitors.

6. The use of any one of the scutellarin derivatives or pharmaceutically acceptable salts thereof according to claims 1-3 in the preparation of a medicament for treating diseases related to IGF2BP2 protein dysfunction.

7. The application according to claim 6, characterized in that, The diseases associated with IGF2BP2 protein dysfunction are breast cancer, colorectal cancer, pancreatic cancer, hepatocellular carcinoma, acute myeloid leukemia, T-cell acute lymphoblastic leukemia, or nasopharyngeal carcinoma.

8. A pharmaceutical composition, characterized in that, The active ingredient of the pharmaceutical composition includes any one of the following: a derivative of scutellarin or a pharmaceutically acceptable salt thereof, as described in any one of claims 1-3.

9. The pharmaceutical composition according to claim 8, characterized in that, The pharmaceutical composition also includes a pharmaceutically acceptable carrier.

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