Altecurinine 15-substituted derivative and anti-tumor application thereof

Abstract

The invention discloses an allosecurinine 15-substituted derivative and anti-tumor application thereof, and belongs to the technical field of medicines. The invention discloses a group of securinine 15-substituted derivative compounds AH-1-AH-29 and anti-tumor application thereof. The securinine 15-substituted derivative compounds AH-1-AH-29 can be applied to preparation of medicines for treating leukemia and / or gastric cancer, prostatic cancer and ovarian cancer. Wherein AH-26 shows the effect of promoting tumor cell apoptosis, and compared with the existing antitumor drugs, the AH-26 has stronger activity and higher selectivity.

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and specifically relates to 15-substituted derivatives of allophylline and their anti-tumor application. Background Art

[0002] Cancer is a major public health problem in the world today and the second leading cause of death in the global population. The survival rate is low, so effective anti-tumor drugs are urgently needed. The search for anti-tumor active chemical components with high efficiency and low toxicity from natural products has always been a hot topic in modern tumor drug research. The natural product allophylline is a plant-derived indolizidine alkaloid with biological activity. At present, there are few research reports related to allophylline, and only a small number of total synthesis studies have been reported. Summary of the invention

[0003] In order to solve the shortcomings and deficiencies of the prior art, a 15-substituted derivative of allelopathic spatholobiline is provided.

[0004] Another object of the present invention is to provide the application of the above-mentioned 15-substituted derivatives of allelopathic spathuline.

[0005] In order to achieve the above-mentioned object of the invention, the present invention adopts the following technical solutions:

[0006] The 15-substituted derivative of allophylline is a compound having the structure shown in Formula I:

[0007]

[0008] In the formula, R represents any one of o-, m-, p-substituted halogen, disubstituted halogen, disubstituted methoxy, acetyl, nitro, methoxyformyl, trifluoromethyl, methoxy, ethyl, tert-butyl, isopropyl, phenyl, and benoxy.

[0009] Further, the 15-substituted derivative of allophylline is any one of compounds AH-1, AH-2, AH-3, AH-4, AH-5, AH-6, AH-7, AH-8, AH-9, AH-10, AH-11, AH-12, AH-13, AH-14, AH-15, AH-16, AH-17, AH-18, AH-19, AH-20, AH-21, AH-22, AH-23, AH-24, AH-25, AH-26, AH-27, AH-28, and AH-29; preferably AH-26; compounds AH-1 to AH-29 are compounds having the following structures respectively:

[0010]

[0011] The pharmaceutically acceptable salt of the 15-substituted derivative of allelopathic spathuline.

[0012] Furthermore, the anion of the pharmaceutically acceptable salt is an inorganic anion or an organic anion; the inorganic anion is chloride, bromide, iodide, sulfate, nitrate, nitrite, phosphate or hydrogen phosphate, etc.; the organic anion is acetate, propionate, cinnamate, toluenesulfonate, citrate, lactate or gluconate, etc.

[0013] Application of the above-mentioned allophylline 15-substituted derivative or its pharmaceutically acceptable salt in the preparation of anti-tumor drugs.

[0014] Furthermore, the tumor includes any one or more of leukemia, ovarian cancer, gastric cancer, and prostate cancer.

[0015] Furthermore, the anti-tumor drug is a drug that promotes the activity of Bax protein.

[0016] Furthermore, the anti-tumor drug is a drug that antagonizes the malignant proliferation of tumors caused by the expression of Bcl-XL, Bcl-2, TAZ, GLI1, MCL1, XIAP, YAP1, β-catenin, c-Myc, p-AKT, JAK1 / 2, STAT3 and / or p-STAT3 proteins.

[0017] Further, in the application, the 15-substituted derivative of allelopathic quinine can be made into a variety of dosage forms with pharmaceutically acceptable excipients using common techniques, including solid dosage forms, semisolid dosage forms, liquid dosage forms and aerosol dosage forms. Specific dosage forms in these types of dosage forms include tablets, pills, granules, lozenges, ointments, solutions, suppositories, injections, inhalants and sprays. Among them, the spray is realized by a pressurizer and an ejector or a dry powder inhalation device. Suitable ejectors such as dichlorodifluoromethane, fluorotrichloromethane, dichlorotetrafluoroethane, carbon dioxide and dimethyl ether can be used as ejectors. The dosage of the spray can be adjusted by the valve of the ejector. These dosage forms can be used for local or systemic administration and can be used for rapid release or sustained release administration. There are many ways to administer this type of drug. In addition to the above methods, there are also oral administration, buccal administration, rectal administration, peritoneal administration, epidermal administration, subcutaneous injection administration and intratracheal administration.

[0018] When administered by subcutaneous injection, such compounds can be formulated into solutions, suspensions and emulsions using water-soluble or fat-soluble solvents. Fat-soluble solvents specifically include vegetable oils and similar oils, synthetic fatty acid glycerides, higher fatty acid esters and glycol esters.

[0019] When administered orally, the compound can be made into a complex with a pharmaceutically acceptable excipient using common techniques. These excipients can make these compounds into a variety of dosage forms that can be accepted by patients, such as tablets, pills, suspensions, gels, etc. There are many methods for preparing oral preparations, such as first mixing the compound with a solid excipient, grinding the mixture thoroughly, adding appropriate excipients, and processing it into granules. Excipients that can be used to make oral dosage forms include: sugars such as lactose, sorbitol, mannitol or sorbitol; celluloses such as corn starch, wheat starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxymethylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, etc.

[0020] The method for preparing the 15-substituted derivative of allophylline is to subject allophylline and a substituted iodobenzene containing an R group to a Heck reaction to obtain the target product; the method specifically comprises the following steps:

[0021] S1. In an inert gas atmosphere, heat and dissolve allophylline in an organic solvent; add a catalyst, a substituted iodobenzene containing an R group and potassium carbonate, stir and react to obtain a mixed solution;

[0022] S2, filtering the mixed solution, washing the filter residue, drying the collected filtrate and then decompressing and drying under reduced pressure to obtain a crude product; separating and purifying by silica gel column chromatography to obtain the target product.

[0023] Furthermore, the organic solvent in step S1 is any one of anhydrous 1,4-dioxane and methanol.

[0024] Furthermore, the catalyst described in step S1 is a Pd(OAc)2 and dppp system; preferably a 5mol% Pd(OAc)2 and 5mol% dppp system.

[0025] Furthermore, the molar ratio of allophylline to iodobenzene containing an R group in step S1 is 1-2:1-2.

[0026] Furthermore, the heating temperature in step S1 is 80±5°C.

[0027] Furthermore, the stirring reaction time in step S1 is 8±1 hours.

[0028] Furthermore, the reagent used for flushing in step S2 is dichloromethane.

[0029] Furthermore, the drying reagent used in step S2 is anhydrous sodium sulfate.

[0030] Compared with the prior art, the present invention has the following advantages and effects:

[0031] The present invention uses natural products as lead compounds, uses organic chemistry and medicinal chemistry to conduct structural modification research, and searches for new drug lead compounds from them, which is one of the innovative models for conducting innovative drug research. The present invention uses natural allophylline as a precursor compound for chemical modification to obtain a series of novel allophylline derivatives. Through pharmacodynamic evaluation of leukemia cells, gastric cancer cells, prostate cancer cells, and ovarian cancer cells in vitro models, it was found that the novel allophylline derivatives have anti-proliferative effects on a variety of cancer cells, can promote cancer cell apoptosis, and are more active and more selective than the existing anti-tumor drug camptothecin.

[0032] The present invention provides a compound with a completely new structure, and the synthetic route adopted uses green chemical reactions, which is more environmentally friendly and more economical in raw materials. These compounds can be used to develop new drugs for treating leukemia, gastric cancer, prostate cancer, and ovarian cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 The synthetic route of 15-substituted derivatives of allelopathic spathuline is shown in the figure.

[0034] Figure 2 These are the results of apoptosis detection after compound AH-26 acted on NB4 (a-d), K562 (e-h), HL-60 (i-l), and U937 (m-p) cells for 48 hours.

[0035] Figure 3 These are the results of apoptosis detection after compound AH-26 acted on HGC-27 (a-d) and SKOV3 (e-h) cells for 48 hours.

[0036] Figure 4 These are the results of mitochondrial membrane potential detection after compound AH-26 acted on NB4 (a~d), K562 (e~h), HL-60 (i~l), and U937 (m~p) cells for 48 hours.

[0037] Figure 5 These are the results of mitochondrial membrane potential detection after compound AH-26 acted on HGC-27 (a~d) and SKOV3 (e~h) cells for 48 hours.

[0038] Figure 6 The graphs show the results of cell cycle detection after compound AH-26 acted on NB4 (a-d) and HL-60 (e-h) cells for 48 hours.

[0039] Figure 7 The graphs show the results of cell cycle detection after compound AH-26 acted on HGC-27 (a-d) and SKOV3 (e-h) cells for 48 hours.

[0040] Figure 8The results of protein expression change detection after AH-26 acted on NB4 (a) and HL-60 (b) cells for 48 hours.

[0041] Fig. 9 The results of protein expression change detection after AH-26 acted on SKOV3 (a) and HGC-27 (b) cells for 48 hours. DETAILED DESCRIPTION

[0042] The present invention is further described in detail below in conjunction with embodiments and drawings, but the embodiments of the present invention are not limited thereto.

[0043] Example 1: Preparation of AH-1 to AH-29

[0044]

[0045] Heck reaction of allelochemicals with substituted iodobenzenes: weigh allelochemicals (150 mg, 0.69 mmol) and add them to a double-necked flask filled with nitrogen and containing 5 mL of ultra-dry 1,4-dioxane, heat to 80 ° C, stir to dissolve, add Pd (OAc) 2 and dppp. Then add substituted iodobenzenes (1.04 mmol) and potassium carbonate (1.04 mmol), stir and react for 8 hours. The reaction was monitored by TLC plate. After about 8 hours, the reaction stopped because the reaction did not proceed. Then filter and rinse the residue with dichloromethane. The collected filtrate was dried over anhydrous sodium sulfate for 5 minutes and then dried under reduced pressure to obtain a crude product. The target products AH-1 to AH-29 were obtained by silica gel column chromatography separation and purification, and the yields varied from 30% to 80%.

[0046] Characterization of compound AH-1 by hydrogen NMR spectrum, carbon NMR spectrum and high-resolution mass spectrometry: 1 H NMR (400MHz, CDCl3) δ7.36(q,J=7.2Hz,2H),7.22-7.10(m,2H),6.81(s,1H),5.78(s,1H),4.38(d,J=5.8Hz,1H),3.67(dd,J=13.0,3.3Hz,1H ),2.81(dd,J=9.5,5.0Hz,1H),2.69(td,J=10.2,5.1Hz,1H),2.59-2.53(m,1H),2.13(d,J=9.8Hz,1H),1.61-1.58(m,4H),1.46-1.38(m,2H). 13C NMR (101MHz, CDCl3) δ172.84,167.24,131.04,130.95,128.86,124.73,124.70,120.94,1 16.73,116.50,109.12,91.12,62.26,60.83,44.27,42.95,22.34,20.76,18.86.HR-ESIMS m / z 312.1411[M+H] + ,calcd for C 19 H 19 FNO2 + 312.1400.

[0047] Characterization of compound AH-2 by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrometry: 1 H NMR (400MHz, CDCl3) δ7.45-7.32(m,2H),7.27-7.23(m,1H),7.10(dt,J=8.0,3.9Hz,1H),6.90(d,J=1.9Hz,1H),5.82(s,1H),4.48(d,J=4.6Hz,1H), 3.69(dd,J=13.1,3.2Hz,1H),2.83(dd,J=9.9,4.6Hz,2H),2.74-2.54(m,2 H),2.06(d,J=9.9Hz,1H),1.72-1.58(m,3H),1.41(dd,J=8.3,4.1Hz,2H). 13 C NMR (101MHz, CDCl3) δ172.68,166.95,164.26,161.80,156.40,140.42,130.68,121.83,117.76,1 16.75,113.10,109.37,90.98,61.54,60.64,43.93,42.36,29.68,21.84,21.13,18.47.HR-ESIMS m / z 312.1375[M+H] + ,calcd for C 19 H 19 FNO2 + 312.1400.

[0048] Compound AH-3 was characterized by hydrogen NMR spectrum, carbon NMR spectrum and high-resolution mass spectrometry: 1H NMR (400MHz, CDCl3) δ7.55(dd,J=8.9,5.2Hz,2H),7.11(t,J=8.6Hz,2H),6.83(d,J=1.9Hz,1H),5.77(s,1H),4.45(d,J=2.6Hz,1H),3.6 8(dd,J=12.9,3.3Hz,1H),2.82(dd,J=9.9,4.6Hz,1H),2.65-2.60(m,2H),2.05(d,J=9.8Hz,1H),1.71-1.57(m,4H),1.44-1.37(m,2H). 13 CNMR(101MHz,CDCl3)δ172.91,167.39,156.99,133.87,129.03,128.08,127.99,126.08,11 6.25,116.03,109.12,91.02,61.74,60.74,44.05,42.49,22.06,21.16,18.54.HR-ESIMSm / z 310.1274[MH] + ,calcd for C 19 H 18 FNO2 + 310.1244.

[0049] Compound AH-4 was characterized by hydrogen NMR spectrum, carbon NMR spectrum and high-resolution mass spectrometry: 1 H NMR (400MHz, CDCl3) δ7.53(d,J=2.6Hz,1H),7.45-7.41(m,1H),7.37(dd,J=4.9,1.8Hz,2H),6.89(d,J=1.9Hz,1H),5.81(s,1H),4.45(d,J=4.5Hz, 1H),3.69(dd,J=13.0,3.1Hz,1H),2.84(dd,J=9.9,4.8Hz,1H),2.69-2.5 7(m,2H),2.06(d,J=9.8Hz,1H),1.70-1.62(m,4H),1.41(d,J=8.3Hz,2H). 13 C NMR (101MHz, CDCl3) δ172.72,167.01,156.66,140.15,135.15,130.29,129.65,126.17,1 24.25,117.82,109.35,91.03,61.64,60.73,44.10,41.62,22.04,21.22,18.54.HR-ESIMS m / z 328.1107[M+H] +,calcd for C 19 H 19 ClNO2 + 328.1104.

[0050] Compound AH-5 was characterized by hydrogen NMR spectrum, carbon NMR spectrum and high-resolution mass spectrometry: 1 H NMR (400MHz, CDCl3) δ7.40-7.35(m,2H),7.29-7.25(m,2H),6.75(d,J=1.9Hz,1H),5.67(s,1H),4.34(d,J=2.6Hz,1H),3.56(dd, J=13.1,3.2Hz,1H),2.70(dd,J=9.9,4.8Hz,1H),2.53-2.44(m,2H),1.93(d,J=9.9Hz,1H),1.59-1.44(m,4H),1.32-1.25(m,2H). 13 C NMR (101MHz, CDCl3) δ172.83,167.19,156.70,136.67,135.89,129.28,127.33,1 17.05,108.89,91.00,61.52,60.68,43.98,42.40,21.96,21.12,18.45.HR-ESIMS m / z 328.1070[M+H] + ,calcd forC 19 H 19 ClNO2 + 328.1104.

[0051] Compound AH-6 was characterized by hydrogen NMR spectrum, carbon NMR spectrum and high-resolution mass spectrometry: 1 H NMR (400MHz, CDCl3) δ7.59-7.51(m,2H),7.46-7.38(m,2H),6.88(d,J=1.8Hz,1H),5.79(s,1H),4.44(d,J=2.4Hz,1H),3.68(dd,J =13.0,3.1Hz,1H),2.82(dd,J=10.3,5.1Hz,1H),2.67-2.54(m,2H),2.05(d,J=9.8Hz,1H),1.84-1.49(m,4H),1.47-1.35(m,2H). 13C NMR (101MHz, CDCl3) δ172.86,167.24,156.94,137.20,132.27,127.59,124.21,1 17.08,108.43,91.05,61.55,60.74,44.07,42.47,22.07,21.19,18.55.HR-ESIMS m / z 372.0611[M+H] + ,calcd forC 19 H 19 BrNO2 + 372.0599.

[0052] Compound AH-7 was characterized by hydrogen NMR spectrum, carbon NMR spectrum and high-resolution mass spectrometry: 1 H NMR (400MHz, CDCl3) δ8.29(d,J=8.9Hz,2H),7.72(d,J=9.0Hz,2H),7.00(d,J=1.9Hz,1H),5.91(s,1H),4.48(d,J=2.4Hz,1H),3.71(dd,J=13.0,3. 1Hz,1H),2.88(dd,J=9.6,5.1Hz,1H),2.71-2.57(m,2H),2.11(d,J=9.9Hz,1H),1.67(ddd,J=15.0,12.0,6.1Hz,4H),1.44(dd,J=8.8,4.1Hz,2H). 13 C NMR (101MHz, CDCl3) δ172.38,166.36,155.96,148.10,144.47,127.62,124.32,1 19.89,110.72,90.98,62.03,60.51,43.74,43.23,22.82,21.43,18.02.HR-ESIMS m / z 339.1417[M+H] + ,calcd for C 19 H 19 N2O4 + 339.1345.

[0053] Compound AH-8 was characterized by hydrogen NMR spectrum, carbon NMR spectrum and high-resolution mass spectrometry: 1H NMR(400MHz, CDCl3) δ8.15(t,J=1.8Hz,1H),7.96(dt,J=7.8,1.4Hz,1H),7.75(ddd ,J=7.9,2.1,1.1Hz,1H),7.54(t,J=7.8Hz,1H),6.95(d,J=1.8Hz,1H),5.82(s,1H), 4.54(d,J=3.6Hz,1H), 3.69(dd,J=13.1,3.2Hz,1H), 2.84(dd,J=10.2,4.3Hz,1H), 2.64(s,5H),2.08(d,J=9.9Hz,1H),1.74-1.55(m,4H),1.41(dd,J=9.1,4.1Hz,2H). 13 C NMR (101MHz, CDCl3) δ197.50,172.79,167.11,157.05,138.95,137.73,130.36,129.55,129.43,1 25.61,117.90,109.30,91.07,61.66,60.73,44.05,42.47,26.77,21.98,21.18,18.47.HR-ESIMS m / z336.1605[M+H] + ,calcd for C 21 H 22 NO3 + 336.1600.

[0054] Compound AH-9 was characterized by hydrogen NMR spectrum, carbon NMR spectrum and high-resolution mass spectrometry: 1 H NMR (400MHz, CDCl3) δ7.98(d,J=8.6Hz,2H),7.63(d,J=8.6Hz,2H),6.96(d,J=1.9Hz,1H),5.83(s,1H),4.50(d,J=6.5Hz,1H),3.67(dd,J=12.9, 3.2Hz,1H),2.83(dd,J=9.9,4.6Hz,1H),2.61(s,5H),2.06(d,J=9.8Hz,1H),1.69-1.54(m,3H),1.44-1.34(m,2H),1.18(dd,J=12.9,5.9Hz,1H). 13C NMR (101MHz, CDCl3) δ197.17,172.63,166.92,156.83,142.47,137.41,128.93,126.21,1 18.51,109.60,91.00,61.48,60.68,44.04,42.40,26.65,22.00,21.20,18.50.HR-ESIMS m / z336.1568[M+H] + ,calcd for C 21 H 22 NO3 + 336.1600.

[0055] Characterization of compound AH-10 by hydrogen NMR spectrum, carbon NMR spectrum and high-resolution mass spectrometry: 1 H NMR (400MHz, CDCl3) δ7.10-7.02(m,2H),6.91-6.80(m,2H),5.84(s,1H),4.37(d,J=2.6Hz,1H),3.67(dd,J=13.0,3.0Hz,1H),2 .83(dd,J=9.9,4.8Hz,1H),2.70-2.55(m,2H),2.04(d,J=9.8Hz,1H),1.74-1.57(m,3H),1.48-1.36(m,2H),1.23-1.12(m,1H). 13 C NMR (101MHz, CDCl3) δ172.54,166.60,164.59,162.11,155.77,141.52,118.53,110.06,1 09.22,108.96,104.91,91.02,61.61,60.76,44.18,42.47,22.14,21.30,18.61.HR-ESIMS m / z 330.1335[M+H] + ,calcd for C 19 H 18 FNO2 + 330.1306.

[0056] Characterization of compound AH-11 by hydrogen NMR spectrum, carbon NMR spectrum and high-resolution mass spectrometry: 1H NMR (400MHz, CDCl3) δ7.37(q,J=8.5Hz,1H),6.96-6.89(m,2H),6.79(s,1H),5.79(s,1H),4.33(s,1H),3.68(d,J=12.6Hz,1H),2.8 1(dd,J=9.9,4.8Hz,1H),2.66(d,J=5.0Hz,1H),2.58(d,J=5.6Hz,1H),2.12(d,J=9.9Hz,1H),1.68-1.64(m,4H),1.46-1.39(m,2H). 13 C NMR (101MHz, CDCl3) δ172.72,167.05,159.92,153.83,140.76,129.87,122.70,120.96,1 12.29,109.43,105.10,91.03,62.79,60.78,43.91,42.30,22.20,21.34,18.75.HR-ESIMS m / z 330.1335[M+H] + ,calcd for C 19 H 18 FNO2 + 330.1306.

[0057] Characterization of compound AH-12 by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrometry: 1 H NMR (400MHz, CDCl3) δ7.24-7.11(m,2H),6.84(s,1H),5.84(s,1H),4.33(d,J=4.3Hz,1H),3.67(d,J=13.1Hz,1H),2. 83(dd,J=9.9,4.8Hz,1H),2.73-2.52(m,2H),2.03(d,J=9.9Hz,1H),1.72-1.58(m,4H),1.41(dd,J=9.9,3.0Hz,2H). 13 C NMR (101MHz, CDCl3) δ172.45,166.36,154.92,152.67,142.76,139.10,134.34,118.29,1 10.51,110.29,110.09,90.90,61.50,60.75,44.22,42.37,22.13,21.27,18.59.HR-ESIMS m / z 348.1223[M+H] + ,calcd forC 19 H 17 F3NO2 +348.1211.

[0058] Compound AH-13 was characterized by hydrogen NMR spectrum, carbon NMR spectrum and high-resolution mass spectrometry: 1 H NMR(400MHz, CDCl3) δ8.06(d,J=8.6Hz,2H),7.67(d,J=8.6Hz,2H),7.19(s,1H) ,5.96(s,1H),5.11(t,J=3.0Hz,1H),3.93(s,3H),3.20(d,J=9.9Hz,1H),2.88( dd,J=11.3,2.7Hz,1H),2.71-2.59(m,2H),2.14(dd,J=11.5,2.4Hz,1H),2.04( s,1H),1.82(ddd,J=13.0,3.8,2.6Hz,1H),1.57(s,4H),1.25(d,J=2.3Hz,2H). 13 C NMR (101MHz, CDCl3) δ172.11,166.57,164.36,143.52,142.29,130.41,130.06,126.15,122. 46,113.50,82.65,73.71,70.83,60.19,56.09,52.29,40.69,25.06,23.81,23.13.HR-ESIMS m / z 352.1572[M+H] + ,calcd forC 21 H 22 NO4 + 352.1549.

[0059] Characterization of compound AH-14 by hydrogen NMR spectrum, carbon NMR spectrum and high-resolution mass spectrometry: 1 H NMR (400MHz, CDCl3) δ7.72-7.62(m,4H),6.93(d,J=1.9Hz,1H),5.85(s,1H),4.47(d,J=2.5Hz,1H),3.70(dd,J=13.0,3.1Hz,1H ),2.86(dd,J=9.8,4.7Hz,1H),2.62(qd,J=10.3,5.0Hz,2H),2.08(d,J=9.8Hz,1H),1.69-1.59(m,4H),1.43(d,J=11.0Hz,2H). 13C NMR (101MHz, CDCl3) δ171.92,167.71,157.27,141.78,131.37,126.39,126.05,126.01,125.0 8,122.60,118.60,109.82,91.05,62.80,60.79,45.66,42.97,24.02,20.52,16.44.HR-ESIMS m / z362.1400[M+H] + ,calcd for C 20 H 19 F3NO2 + 362.1368.

[0060] Characterization of compound AH-15 by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrometry: 1 H NMR (400MHz, CDCl3) δ7.47(q,J=7.9Hz,2H),7.39(s,1H),7.26(s,1H),6.91(d,J=2.0Hz,1H),5.83(s,1H),4.44(d,J=2.6Hz,1H),3.69(dd,J= 13.0,3.1Hz,1H),2.85(dd,J=9.9,4.6Hz,1H),2.72-2.57(m,2H),2.07(d,J=9.9Hz,1H),1.64(dq,J=10.3,5.4,4.6Hz,4H),1.49-1.36(m,2H). 13 C NMR (101MHz, CDCl3) δ172.71,166.95,156.54,149.80,140.39,130.48,124.37,121.85,1 18.64,118.01,109.51,91.05,61.68,60.78,44.13,42.55,22.10,21.24,18.57.HR-ESIMS m / z 378.1314[M+H] + ,calcd for C 20 H 19 F3NO2 + 378.1317.

[0061] Characterization of compound AH-16 by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrometry: 1H NMR (400MHz, CDCl3) δ7.56(s,2H),7.42(d,J=4.1Hz,3H),6.90(s,1H),5.78(d,J=3.4Hz,1H),4.53(s,1H),3.70(d,J=13.0Hz, 1H), 2.84 (d, J=9.8Hz, 1H), 2.65 (d, J=3.4Hz, 2H), 2.07 (dd, J=9.9, 3.3Hz, 1H), 1.65 (d, J=12.9Hz, 4H), 1.41 (d, J=9.6Hz, 2H). 13 C NMR (101MHz, CDCl3) δ173.05,167.63,158.12,138.30,129.81,129.06,126.11,1 16.79,108.46,91.15,61.65,60.75,44.00,42.58,22.02,21.15,18.52.HR-ESIMS m / z 294.1508[M+H] + ,calcd forC 19 H 20 NO2 + 294.1494.

[0062] Compound AH-17 was characterized by hydrogen NMR spectrum, carbon NMR spectrum and high-resolution mass spectrometry: 1 H NMR(400MHz, CDCl3)δ7.36(d,J=6.9Hz,2H),7.33-7.28(m,1H),7.21(d,J=7.4H z,1H),6.88(d,J=1.8Hz,1H),5.76(s,1H),4.51(d,J=4.5Hz,1H),3.68(dd,J=1 3.0,3.3Hz,1H),2.82(dd,J=9.4,5.0Hz,1H),2.66-2.60(m,2H),2.39(s,3H),2 .05(d,J=9.8Hz,1H),1.69-1.58(m,3H),1.44-1.35(m,2H),1.26-1.18(m,1H). 13 C NMR (101MHz, CDCl3) δ173.07,167.71,158.28,138.71,138.27,130.60,128.90,126.69,123. 26,116.59,108.21,91.13,61.60,60.71,43.93,42.54,21.98,21.52,21.10,18.48.HR-ESIMS m / z 308.1634[M+H] +,calcdfor C 20 H 22 NO2 + 308.1651.

[0063] Characterization of compound AH-18 by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrometry: 1 H NMR (400MHz, CDCl3) δ7.47(d,J=8.4Hz,2H),7.27-7.20(m,2H),6.88(dd,J=8.9,1.8Hz,1H),5.76(d,J=12.9Hz,1H),4.53(d,J=4.4Hz,1H),3.68 (dd,J=12.9,3.3Hz,1H),2.81(dd,J=10.3,5.1Hz,1H),2.66-2.58(m,2H ),2.38(s,3H),2.07-2.02(m,1H),1.72-1.54(m,4H),1.43-1.35(m,2H). 13 C NMR (101MHz, CDCl3) δ173.10,167.75,157.71,140.25,135.27,129.75,125.99,115. 80,107.89,91.06,61.35,60.64,43.79,42.39,21.83,21.28,20.99,18.37.HR-ESIMS m / z308.1634[M+H] + ,calcd for C 20 H 22 NO2 + 308.1651.

[0064] Characterization of compound AH-19 by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrometry: 1 H NMR (400MHz, CDCl3) δ7.34(t,J=8.1Hz,1H),7.14(d,J=7.9Hz,1H),7.06(t,J=2.2Hz,1 H),6.94(dd,J=8.6,2.1Hz,1H),6.88(d,J=1.9Hz,1H),5.78(s,1H),4.50(d,J=4.5Hz, 1H),3.84(s,3H),3.68(dd,J=12.9,3.2Hz,1H),3.48(s,1H),2.82(dd,J=9.9,4.6Hz,1 H),2.65(d,J=3.9Hz,1H),2.06(d,J=9.9Hz,1H),1.71-1.57(m,4H),1.44-1.36(m,2H). 13C NMR (101MHz, CDCl3) δ173.00,167.52,159.97,157.82,139.66,130.08,129.07,126.11,118.61,117. 00,114.95,111.98,108.60,91.13,61.68,60.70,55.41,43.94,42.51,21.93,21.13,18.46.HR-ESIMS m / z 324.1611[M+H] + ,calcd for C 20 H 22 NO3 + 324.1600.

[0065] Characterization of compound AH-20 by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrometry: 1 H NMR (400MHz, CDCl3) δ7.36-7.28(m,2H),7.18(d,J=8.0Hz,1H),6.87(d,J=1.8Hz,1H),5.73(s,1H),4.53(d,J=6.5Hz,1H),3.68(dd,J=12.9,3.3Hz ,1H),2.81(dd,J=9.9,4.6Hz,1H),2.63(dd,J=4.1,2.1Hz,2H),2.30(d,J =3.9Hz,6H),2.05(d,J=9.8Hz,1H),1.69-1.60(m,4H),1.45-1.35(m,2H). 13 C NMR (101MHz, CDCl3) δ173.69,167.95,158.07,139.05,137.35,135.82,130.30,127.91,123.64, 115.67,107.74,91.63,61.40,60.73,43.88,42.50,21.98,21.04,20.02,19.71,18.47.HR-ESIMS m / z 322.1824[M+H] + ,calcd for C 21 H 24 NO2 + 322.1807.

[0066] Characterization of compound AH-21 by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrometry: 1H NMR (400MHz, CDCl3) δ7.54(d,J=8.4Hz,2H),7.24(d,J=8.3Hz,2H),7.10(s,1 H),5.87(s,1H),5.12(t,J=3.0Hz,1H),3.19(d,J=11.6Hz,1H),2.85(dd,J=1 1.4,2.8Hz,1H),2.71-2.58(m,4H),2.13(dd,J=11.4,2.4Hz,1H),1.81(dt,J =13.0,3.1Hz,1H),1.64(q,J=2.7Hz,2H),1.56(s,4H),1.25(d,J=2.9Hz,3H). 13 C NMR (101MHz, CDCl3) δ172.58,165.18,145.86,144.68,135.27,128.40,126.22,120.07,111.98 ,82.72,74.15,70.82,56.09,40.90,31.52,29.72,28.69,25.08,23.81,23.20,16.35.HR-ESIMS m / z 322.1824[M+H] + ,calcd for C 21 H 24 NO2 + 322.1807.

[0067] Characterization of compound AH-22 by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrometry: 1 H NMR (400MHz, CDCl3) δ7.52(d,J=7.1Hz,2H),7.43(d,J=7.2Hz,2H),6.89(s,1H),5.75(s,1H),4.55(d,J=4.6Hz,1H),3.73-3.65(m,1H), 2.82(dd,J=9.9,4.7Hz,1H),2.72-2.61(m,2H),2.04(d,J=9.9Hz,1H),1.73-1.56(m,4H),1.38(d,J=17.3Hz,2H),1.33(d,J=1.2Hz,9H). 13C NMR (101MHz, CDCl3) δ173.12,167.79,157.72,153.39,135.14,126.01,125.87,115.91,10 7.94,91.08,61.38,60.75,43.88,42.53,34.81,31.13,21.88,21.01,18.38.HR-ESIMSm / z 350.2134[M+H] + ,calcd for C 23 H 28 NO2 + 350.2120.

[0068] Characterization of compound AH-23 by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrometry: 1 H NMR (400MHz, CDCl3) δ7.35(dd,J=3.6,1.3Hz,2H),7.23-7.13(m,2H),6.47(s,1H),5.74(s,1H),4.03(d,J=5.4Hz,1H),3.66(dd,J=12.7,2.9Hz,1H ),2.89-2.78(m,3H),2.61-2.51(m,1H),2.18(d,J=9.6Hz,1H),1.69-1.6 0(m,4H),1.49-1.40(m,2H),1.34(d,J=5.8Hz,3H),1.13(d,J=6.8Hz,3H). 13 C NMR (101MHz, CDCl3) δ172.95,167.40,145.90,139.19,134.76,129.06,127.77,126.18,126.05,120 .10,108.41,91.04,65.05,61.19,44.49,43.06,30.95,24.78,23.92,22.85,21.78,19.36.HR-ESIMS m / z 336.1980[M+H] + ,calcd for C 22 H 26 NO2 + 336.1964.

[0069] Characterization of compound AH-24 by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrometry: 1H NMR (400MHz, CDCl3) δ8.05 (s, 1H), 7.90-7.83 (m, 3H), 7.67 (dd, J = 8.8, 2.0Hz, 1H),7.54(dt,J=6.4,3.6Hz,2H),7.04(d,J=2.0Hz,1H),5.81(s,1H),4.72(d,J =4.0Hz,1H),3.73(dd,J=13.0,3.3Hz,1H),2.89(dd,J=9.9,4.6Hz,1H),2.72- 2.62(m,2H),2.13(d,J=9.9Hz,1H),1.62-1.59(m,4H),1.44(d,J=10.1Hz,2H). 13 C NMR (101MHz, CDCl3) δ173.63,158.50,135.14,133.85,133.58,129.10,128.86,127.82,127.5 5,127.09,126.31,123.32,117.17,61.62,60.93,44.18,42.60,21.79,21.30,18.57.HR-ESIMS m / z 344.1674[M+H] + ,calcd forC 23 H 22 NO2 + 344.1651.

[0070] Compound AH-25 was characterized by hydrogen NMR spectrum, carbon NMR spectrum and high-resolution mass spectrometry: 1 H NMR (400MHz, CDCl3) δ7.21(d,J=8.4Hz,1H),6.64(s,1H),6.55-6.47(m,2H),5.66(s,1H),4.45(s,1H),3.84(d,J=3.6Hz,6H),3.65( d,J=13.3Hz,1H),2.71(ddd,J=28.3,9.6,5.1Hz,2H),2.55-2.47(m,1H),2.11(d,J=9.8Hz,1H),1.59(s,4H),1.41(d,J=15.0Hz,2H). 13C NMR (101MHz, CDCl3) δ176.90,173.37,161.87,158.14,129.70,118.78,109.45,107.00,104.94 ,98.96,95.60,91.46,62.66,61.36,55.52,55.48,43.64,42.25,22.22,20.98,18.83.HR-ESIMS m / z 354.1719[M+H] + ,calcd for C 21 H 24 NO4 + 354.1705.

[0071] Compound AH-26 was characterized by hydrogen NMR spectrum, carbon NMR spectrum and high-resolution mass spectrometry: 1 H NMR (400MHz, CDCl3) δ6.88(d,J=1.9Hz,1H),6.67(d,J=2.1Hz,2H),6.50(t,J=2.2Hz,1H),5.78(s,1H),4.51(d,J=2.8Hz,1H),3.83(s ,6H),2.82(dd,J=9.6,4.3Hz,1H),2.73-2.57(m,3H),2.05(d,J=9.9Hz,1H),1.87-1.74(m,1H),1.72-1.57(m,4H),1.44-1.41(m,1H). 13 C NMR (101MHz, CDCl3) δ172.99,167.51,161.11,158.08,140.29,117.05,108.64,104. 49,101.31,90.78,61.75,60.71,55.51,43.98,42.58,22.05,21.17,18.54.HR-ESIMS m / z354.1758[M+H] + ,calcd for C 21 H 24 NO4 + 354.1705.

[0072] Characterization of compound AH-27 by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrometry: 1H NMR (400MHz, CDCl3) δ7.45-7.31(m,6H),7.15(d,J=8.5Hz,2H),7.01(d,J=8 .0Hz,1H),6.86(s,1H),5.77(s,1H),5.10(s,2H),4.46(d,J=4.8Hz,1H),3.6 7(d,J=13.0Hz,1H),2.81(dd,J=9.9,4.7Hz,1H),2.69-2.55(m,2H),2.04(d, J=9.9Hz,1H),1.69-1.55(m,3H),1.38(d,J=12.4Hz,2H),1.28-1.12(m,1H). 13 C NMR (101MHz, CDCl3) δ172.95,167.50,159.06,157.91,139.68,136.46,130.03,128.63,128.12,127.41,118. 78,116.91,115.81,112.94,108.46,91.09,70.12,61.63,60.67,43.88,42.50,21.97,21.09,18.47.HR-ESIMS m / z 400.1938[M+H] + ,calcd for C 26 H 26 NO3 + 400.1913.

[0073] Compound AH-28 was characterized by hydrogen NMR spectrum, carbon NMR spectrum and high-resolution mass spectrometry: 1 H NMR(400MHz, CDCl3)δ7.54(d,J=8.9Hz,2H),7.45-7.34(m,5H),7.01(d,J=9.0Hz ,2H),6.82(s,1H),5.72(s,1H),5.11(s,2H),4.52(d,J=4.6Hz,1H),3.68(dd,J=1 2.9,3.3Hz,1H),2.81(dd,J=9.8,4.7Hz,1H),2.63(td,J=11.6,11.1,5.3Hz,2H) ,2.04(d,J=9.8Hz,1H),1.70-1.57(m,3H),1.47-1.35(m,2H),1.26-1.17(m,1H). 13C NMR (101MHz, CDCl3) δ173.22,167.90,160.19,157.26,136.33,130.77,128.69,128.21,127.64,127. 45,115.30,114.76,107.38,91.02,70.12,61.31,60.75,43.85,42.41,22.37,20.98,18.42.HR-ESIMS m / z 400.1938[M+H] + ,calcd for C 26 H 26 NO3 + 400.1913.

[0074] Compound AH-29 was characterized by hydrogen NMR spectrum, carbon NMR spectrum and high-resolution mass spectrometry: 1 H NMR (400MHz, CDCl3) δ7.33-7.27(m,2H),7.19(t,J=8.8Hz,2H),6.47(s,1H),5.73(s,1H),4.07(d,J=5.1Hz,1H),3.68-3.63(m,1H),2. 82(dq,J=10.1,5.5Hz,2H),2.63-2.53(m,3H),2.18(d,J=9.6Hz,1H),1.60-1.58(m,4H),1.44(d,J=7.9Hz,2H),1.23(t,J=7.6Hz,3H). 13 C NMR (101MHz, CDCl3) δ172.68,164.40,141.53,140.36,138.18,129.01,128.88,127.74,126.12, 120.26,108.08,90.34,65.47,61.95,45.92,42.97,26.57,22.90,21.74,19.33,15.18.HR-ESIMS m / z322.1824[M+H] + ,calcd for C 21 H 24 NO2 + 322.1807.

[0075] Example 2: Antitumor activity assay

[0076] All cells were cultured in a 37°C, 5% CO2 incubator. The culture medium composition of human acute promyelocytic leukemia cells NB4, human histiocytic lymphoma cells U937, human chronic myeloid leukemia cells K562, and gastric cancer cell MNK45 is: RPMI-1640 medium + 10% FBS + 1% double antibody. The culture medium composition of human myeloid leukemia cells HL-60 is: IMDM medium + 20% FBS + 1% double antibody. The culture medium composition of human ovarian cancer cell SKOV3 is: high glucose DMEM medium + 10% FBS + 1% double antibody. Human gastric cancer cells (undifferentiated) HGC-27, human pancreatic cancer cells PANC-1: DMEM medium + 10% FBS + 1% double antibody.

[0077] (1) MTT assay steps: SKOV3, MNK45, HGC-27, and PANC-1 cells in the logarithmic growth phase were digested and centrifuged, the supernatant was discarded, the cells were resuspended and counted, and the number of cells was calculated as 1×10 5 / mL of cells were inoculated in a 96-well plate and cultured overnight until the cells adhered to the wall. The next day, the old culture medium was removed and 100μL of culture medium containing drug solution was added. After culturing in the incubator for a specific time of 72h, 20μL of MTT solution (5mg / mL) was added to each well and incubated in the incubator for 4 hours. The supernatant was removed and 120μL of DMSO was added to each well. The plates were shaken for 5 minutes and the absorbance was measured at a wavelength of 490nm using an enzyme marker. The inhibition rate was calculated as follows [=(OD 空白 -OD 实验 ) / OD 空白 ×100%】and IC 50 (Calculated using GraphPad software). MTT results showed that allelopathic sclerotin and most of its derivatives could inhibit the growth of tumor cells. Among them, the most active compound AH-26 had an IC 50 It is 0.01-0.49μM, which is stronger than the positive drug camptothecin.

[0078] (2) CCK8 experimental steps: NB4, HL-60, U937, and K562 cells in the logarithmic growth phase were centrifuged, the supernatant was discarded, the cells were resuspended and counted, and the number of cells was calculated as 1×10 5 / mL of cells were inoculated in a 96-well plate, 50 μL of cell suspension was added to each well, and then 50 μL of medium containing drug solution was added. After culturing in an incubator for a specific time of 72 hours, 10 μL of CCK8 solution was added to each well, incubated in an incubator for 2 hours, and the absorbance was measured at a wavelength of 450 nm using an enzyme marker. Calculate the inhibition rate [= (OD 空白 -OD 实验 ) / (OD 空白 -OD 培养基 )×100%】and IC 50(Calculated using GraphPad software). CCK8 results showed that allelopathic schizophylline and its derivatives exhibited excellent antitumor activity, among which the most active compound AH-26 had an IC of 1.34 for myeloid leukemia cells. 50 The activity was 0.16-0.42 μM, which was stronger than the positive control camptothecin.

[0079] Table 1. Antitumor activity of AH-1 to AH-29

[0080]

[0081]

[0082] Example 3: Study on inducing tumor cell apoptosis

[0083] The cell culture method (NB4, HL-60, U937, K562, SKOV3, HGC-27) was referred to Example 3. Cells in the logarithmic phase were seeded in 6-well plates, and 1×10 5 Cells / well were added, and the compound was added for 48 hours. The mixture was centrifuged at 1000 rpm for 5 minutes, and the supernatant was discarded. The cells were collected, and 100 μL Annexin V Binding Buffer was added to resuspend the cells. Then, 2.5 μL Annexin V-FITC Reagent and 2.5 μL PI Reagent were added. After gentle vortex mixing, 400 μL Annexin V Binding Buffer was added after incubation at room temperature in the dark for 20 minutes, and the sample was mixed. Appropriate flow cytometer detection parameters were set and the flow cytometer was used for detection. The results showed that AH-26 could significantly induce leukemia cells to enter apoptosis, and it was concentration-dependent ( Figure 2 , Figure 3 ).

[0084] Example 4: Study on the effect on mitochondrial membrane potential of tumor cells

[0085] The cell culture method (NB4, HL-60, U937, K562, SKOV3, HGC-27) was referred to Example 3. Cells in the logarithmic phase were seeded in 6-well plates, and 1×10 5cells / well, added the compound for 48 hours, centrifuged at 1200rpm for 5 minutes, discarded the supernatant, collected the cells, added 0.5mL JC-1 staining working solution, and inverted several times to mix. After incubation at 37℃ in a cell culture incubator for 20 minutes, centrifuged at 600×g at 4℃ for 4 minutes, and collected the cells. Washed twice with JC-1 staining buffer, and finally resuspended with 200μL JC-1 staining buffer, set the appropriate flow cytometer detection parameters, and tested on the machine. The results showed that the mitochondrial membrane potential of NB4, HL-60, U937, K562, SKOV3, and HGC-27 cells after AH-26 treatment was significantly reversed, and it was concentration-dependent, indicating that AH-26 promoted mitochondrial pathway-mediated apoptosis of tumor cells ( Figure 4 , Figure 5 ).

[0086] Example 5: Study on the effect on tumor cell cycle

[0087] The cell (NB4, HL-60, SKOV3, HGC-27) culture method was referred to Example 3. Cells in the logarithmic phase were seeded in 6-well plates, 1×10 5 cells / well, add the compound for 48 hours, centrifuge at 1000rpm for 5 minutes, discard the supernatant, collect the cells, add 500μL 70% pre-cooled ethanol at 4℃ to fix overnight, collect the cells by centrifugation, add 100μL RNase A solution, resuspend the cells, and bathe at 37℃ for 30min. Then add 400μL PI staining solution and mix well, incubate at 4℃ in the dark for 30min. Set appropriate flow cytometer detection parameters and detect on the machine. The results showed that NB4, HL-60, SKOV3, and HGC-27 cells were arrested in the G1 phase after AH-26, indicating that compound AH-26 inhibits the tumor cell cycle and thus inhibits tumor cell proliferation ( Figure 6 , Figure 7 ).

[0088] Example 6: Study on the effect on tumor cell protein expression

[0089] The cell (NB4, HL-60, SKOV3, HGC-27) culture method was referred to Example 3. Cells in the logarithmic phase were seeded in 6-well plates, 1×10 5cells / well, after adding the compound for 48 hours, the cells were collected, the protein samples were extracted, the protein concentration was measured by the BCA method, the protein samples were denatured, electrophoresed, transferred to the membrane, blocked with 5% skim milk powder, incubated with primary and secondary antibodies, developed, and detected chemiluminescence with an ultrasensitive chemiluminometer to obtain bands. The results showed that AH-26 promoted the expression of the tumor suppressor protein Bax in tumor cells, with obvious concentration dependence. AH-26 activated Caspase 3 / 9, reduced the expression of the original form of Caspase 3 / 9, and increased the expression of activated Cl-Caspase 3 / 9. AH-26 also inhibited the expression of tumor-promoting proteins Bcl-XL, Bcl-2, TAZ, GLI1, MCL1, XIAP, YAP1, β-catenin, c-Myc, p-AKT, JAK1 / 2, STAT3, and p-STAT3 in tumor cells, also with concentration dependence ( Figure 8 , Fig. 9 ). In conclusion, AH-26 exerts its anti-tumor effect by inhibiting the JAK / STAT3 pathway.

[0090] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the described embodiments. Any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principles of the present invention shall be equivalent replacement methods and shall be included in the protection scope of the present invention.

Claims

1. A 15-substituted derivative of allophylline, characterized in that: A compound having a structure shown in Formula I: In the formula, R represents any one of o-, m-, p-substituted halogen, disubstituted halogen, disubstituted methoxy, acetyl, nitro, methoxyformyl, trifluoromethyl, methoxy, ethyl, tert-butyl, isopropyl, phenyl, and benoxy.

2. The 15-substituted derivative of allophylline according to claim 1, characterized in that: The 15-substituted derivative of allophylline is any one of compounds AH-1, AH-2, AH-3, AH-4, AH-5, AH-6, AH-7, AH-8, AH-9, AH-10, AH-11, AH-12, AH-13, AH-14, AH-15, AH-16, AH-17, AH-18, AH-19, AH-20, AH-21, AH-22, AH-23, AH-24, AH-25, AH-26, AH-27, AH-28, and AH-29; compounds AH-1 to AH-29 are compounds having the following structures:

3. A pharmaceutically acceptable salt of the 15-substituted derivative of allophylline as claimed in claim 1 or 2.

4. The pharmaceutically acceptable salt of the 15-substituted derivative of allophylline according to claim 3, characterized in that: The anion of the pharmaceutically acceptable salt is an inorganic anion or an organic anion; the inorganic anion is chloride, bromide, iodide, sulfate, nitrate, nitrite, phosphate or hydrogen phosphate; the organic anion is acetate, propionate, cinnamate, toluenesulfonate, citrate, lactate or gluconate.

5. Use of the 15-substituted derivative of allophylline as claimed in any one of claims 1 to 2 or the salt as claimed in any one of claims 3 to 4 in the preparation of antitumor drugs.

6. The use according to claim 5, characterized in that: The tumor includes any one or more of leukemia, ovarian cancer, gastric cancer, and prostate cancer.

7. The use according to claim 5, characterized in that: The anti-tumor drug is any one or more of the following: I. Drugs that promote Bax protein activity; II. Drugs that antagonize the malignant proliferation of tumors caused by the expression of Bcl-XL, Bcl-2, TAZ, GLI1, MCL1, XIAP, YAP1, β-catenin, c-Myc, p-AKT, JAK1 / 2, STAT3 and / or p-STAT3 proteins; III. Drugs for the treatment of gastric cancer; IV. Drugs for the treatment of prostate cancer; V. Drugs for the treatment of ovarian cancer; VI. Drugs for the treatment of leukemia; VII. Drugs that promote apoptosis of tumor cells.

8. The method for preparing the 15-substituted derivative of allophylline according to claim 1 or 2, characterized in that: The steps include: S1. In an inert gas atmosphere, heat and dissolve allophylline in an organic solvent; add a catalyst, a substituted iodobenzene containing an R group and potassium carbonate, stir and react to obtain a mixed solution; S2, filtering the mixed solution, washing the filter residue, drying the collected filtrate and then decompressing and drying under reduced pressure to obtain a crude product; separating and purifying by silica gel column chromatography to obtain the target product.

9. The preparation method according to claim 8, characterized in that: The organic solvent in step S1 is any one of anhydrous 1,4-dioxane and methanol; The catalyst described in step S1 is Pd(OAc)2 and dppp system; The molar ratio of allophylline to iodobenzene containing an R group in step S1 is 1-2:1-2; the heating temperature in step S1 is 80±5° C.; The stirring reaction time in step S1 is 8±1 hours.

10. The preparation method according to claim 8, characterized in that: The reagent used for washing in step S2 is dichloromethane; The drying reagent used in step S2 is anhydrous sodium sulfate.

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