A bisindolebiphenyl compound and its preparation method and application

Abstract

The present invention discloses a bisindole biphenyl compound, its preparation method, and application, belonging to the field of chemical drugs. The compound has the general structural formula (I). The compound is prepared by using a bisindole biphenyl compound obtained by fermentation of the endophytic fungus GZWMJZ-258 from bamboo plants as a raw material, followed by alkylation and glycosylation. The compound has strong inhibitory activity against the human acute myeloid cell line MV4-11, but weak inhibitory activity against normal human liver cells L-02, and can be used to prepare drugs for the prevention and treatment of leukemia. #imgabs0#

Description

Technical Field

[0001] The present invention belongs to the field of chemical medicines, and in particular relates to a bisindolebiphenyl compound, a preparation method thereof and an application thereof. Background Art

[0002] Leukemia is one of the top ten malignant tumors, accounting for 3.1% of all cancer-related deaths. Leukemia can be divided into two main categories, acute leukemia and chronic leukemia, based on the degree of cell differentiation. In recent years, due to environmental pollution and other factors, the incidence of acute leukemia has been increasing annually among children and young adults. Acute myeloid leukemia (AML) is the most common acute leukemia in adults. AML is a heterogeneous disease characterized by the uncontrolled proliferation of myeloid precursor cells, which gradually replaces normal hematopoiesis in the bone marrow. It is the most lethal type of leukemia. If left untreated, death usually occurs within weeks or months. Drug therapy remains an effective means of controlling the disease. Chemotherapy drugs can kill tumor cells in the short term, but they also cause severe damage to normal cells. Highly effective and low-toxic targeted drugs have become a hot topic in anti-tumor research in recent years.

[0003] The development of safe and effective targeted AML drugs is of great significance. Natural products are endogenous compounds produced by biological metabolism. They are highly compatible with the human body and play a crucial role in the fight against disease, making them a key source of new drug discovery. According to statistics, between 1981 and 2019, two-thirds of the 1,394 new small molecule drugs launched worldwide were related to natural products. In particular, in the field of anti-cancer drug research, 84% of the 185 small molecule anti-cancer drugs were related to natural products. Microbial metabolites are an important component of natural products and a key source of anti-cancer drugs. Furthermore, drugs derived from microorganisms offer inherent advantages in addressing drug source issues. Previous studies have shown that fungal-derived bisindole biphenyl compounds exhibit selective inhibitory activity against the human myeloid leukemia MV4-11 cell line. Further structural modification has significantly improved their selectivity, suggesting their potential as new targeted AML drugs. Summary of the Invention

[0004] The present invention aims to provide a bisindole biphenyl compound and a preparation method thereof, as well as the use of the compound in the preparation of a drug for preventing or treating leukemia, thereby overcoming the disadvantage that existing chemotherapy drugs for acute myeloid leukemia can kill tumor cells in the short term but also cause serious damage to normal cells, and proposing a drug with high efficiency and low toxicity targeting acute myeloid leukemia.

[0005] To achieve the above purpose, the following technical solution is adopted: a bisindole biphenyl compound, the general structural formula of which is formula (I):

[0006]

[0007] Wherein, R1 is selected from ethoxy, cyclopentyloxy, morpholinoethoxy, 1-ethoxy-D-glucose, 3,4-dichloroacetophenoneoxy, acetophenoneoxy, and R2 is selected from cyclopentyl and morpholinoethyl;

[0008] The compound preparation method includes: alkylation and glycosylation reactions, and the specific preparation steps are: dissolving compound A in which R1 and R2 are both hydrogen and compound B in which R1 is hydroxyl and R2 is hydrogen in tetrahydrofuran or N,N-dimethylformamide, then adding potassium hydroxide or potassium carbonate, and performing an alkylation reaction with a corresponding bromoalkane reagent. The compound containing a glycosyl group is further deacetylated under the action of sodium methoxide to obtain the target compound.

[0009] The compound structural formula is any one of formulas 1-8:

[0010]

[0011] The bisindolebiphenyl compound is used for preparing medicine for preventing or treating acute myeloid leukemia.

[0012] The bisindole biphenyl compound is used for preparing a drug for resisting leukemia formed by a human leukemia cell line MV4-11.

[0013] When the compound is used as a medicine, it is used directly or in the form of a pharmaceutical composition. The pharmaceutical composition contains 0.1-99% of the compound, and the rest is a pharmaceutical carrier.

[0014] A medicine for preventing or treating acute myeloid leukemia, comprising the compound of the structural formula 1-8 and a pharmaceutically acceptable carrier.

[0015] The pharmaceutically acceptable carrier is one or more solid, semi-solid and liquid diluents, fillers and pharmaceutical product adjuvants, including fillers, diluents, emulsifiers, disintegrants, binders and drug-carrying carriers without toxic side effects.

[0016] The dosage forms of the medicine are tablets, injections, capsules and granules.

[0017] The present invention offers significant advantages and beneficial effects compared to existing technologies. As demonstrated by the above technical solutions, compounds 1-8 exhibit significant inhibitory activity against the human acute myeloid leukemia cell line MV4-11. Compounds 5 and 6 exhibited stronger selective inhibitory activity against MV4-11 than the marketed drug PKC-412, demonstrating their potential as highly effective, low-toxic drugs for the prevention and treatment of acute myeloid leukemia. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 It is the general structural formula of bisindolebiphenyl compounds;

[0019] Figure 2 It is the structural formula of bisindolebiphenyl compound 1-8. DETAILED DESCRIPTION

[0020] The synthetic raw material compounds A and B in the present invention are isolated from the endophytic fungus GZWMJZ-258 of wood bamboo, and their structures are shown in the figure below.

[0021]

[0022] Example 1 Preparation of Compound 1

[0023] In a 25 mL two-necked reaction flask, compound A (75.0 mg, 0.15 mmol) was added and dissolved with 4 mL of N,N-dimethylformamide. Under argon protection, bromocyclopentane (31.0 μL, 0.3 mmol) and KOH (20.0 mg, 0.36 mmol) were added. The temperature was raised to 40 ° C and stirred for 22 h. The reaction was terminated by cooling to 0 ° C and adding water. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The mixture was purified by preparative high performance liquid chromatography to obtain compound 116.9 mg (yield 19%), and compound A25.4 mg (recovery rate 34%) was recovered.

[0024] 1 H NMR(600MHz,DMSO-d6)δ11.29(d,J=2.5Hz,1H,NH),7.56(d,J=8.5Hz,1H,ArH),7.55(s ,1H,ArH),7.46(d,J=2.4Hz,1H,ArH),7.44(d,J=8.2Hz,1H,ArH),7.43-7.39(m,2H,Ar H),7.16(td,J=7.6Hz,0.9Hz,1H,ArH),7.12(td,J=7.6Hz,0.8Hz,1H,ArH),7.04(t,J= 7.6Hz,1H,ArH),7.01(t,J=7.6Hz,1H,ArH),5.02-4.97(m,1H,cyclopentane-CH2CH2C H CH2CH2),3.45(s,6H,2×OMe),3.42(s,6H,2×OMe),2.25-1.70(m,8H,cyclopentane-C H2 C H2 CHC H2 C H2 ); 13CNMR(150MHz,DMSO-d6)δ147.7(2×C),147.6(2×C),135.9(2×C),127.6,127.1,125.3(2×C),122.3,121.9,120.9( 2×C),120.6,120.3,119.0,118.8,111.4,110.1,107.0,106.7,60.4(4×C),56.3,32.3(2×C),23.7(2×C); HRESIMS calcd for C 31 H 32 N2O4Na519.22543, found 519.22491.

[0025] Example 2 Preparation of Compound 2

[0026] In a 25 mL two-necked reaction flask, compound A (50.0 mg, 0.1 mmol) was added and dissolved in 4 mL of tetrahydrofuran. Under argon protection, 2-(4-)morpholinoethyl bromide (36.0 μL, 0.3 mmol) and KOH (6 mg, 0.11 mmol) were added. The temperature was raised to 40 ° C and stirred for 37 h. The temperature was lowered to 0 ° C and water was added to terminate the reaction. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The mixture was purified by preparative high performance liquid chromatography to obtain compound 227.0 mg (yield 28%) and recovered compound A26.6 mg (recovery rate 35%).

[0027] 1 H NMR (600MHz, DMSO-d6) δ11.32(d,J=2.5Hz,1H,NH),7.62(d,J=8.3Hz,1H,ArH),7.59(s,1H,ArH),7.47(d,J=2.4Hz,1H,ArH),7.45(t,J=7.6Hz,2H,Ar H),7.41(d,J=8.0Hz,1H,ArH),7.24(td,J=7.0Hz,0.9Hz,1H,ArH),7.13-7.09(m,2H,ArH),7.01(td,J=8.0Hz,0.9Hz,1H,ArH),4.70(t,J=6.0,2H,-NC H2 -CH2-morpholine),3.91-3.76(m,4H,morpholine-N(CH2C H2 )2O),3.60-3.54(m,4H,morpholine-N(C H2 CH2)2O),3.45(s,6H,2×OMe),3.43(s,6H,2×OMe),3.33-3.28(m,2H,-N-CH2-CH2 -morpholine); 13 C NMR(150MHz,DMSO-d6)δ147.7(2×C),147.6(2×C),135.9,135.5,128.4,127.7,127.0,125.3,122.6,121.5,121.2,120.9,1 20.8,120.3,119.5,118.7,111.4,109.8,107.6,106.8,63.6(2×C),60.5(2×C),60.3(2×C),54.6,51.7(2×C),40.5; HRESIMS calcd forC 32 H 36 N3O5542.26495, found 542.26453.

[0028] Example 3 Preparation of Compound 3

[0029] In a 25 mL two-necked reaction flask, compound B (150.0 mg, 0.3 mmol) was added and dissolved with 6 mL of N,N-dimethylformamide. Under argon protection, α-bromoacetophenone (106.0 mg, 0.5 mmol) and KOH (56.0 mg, 1.0 mmol) were added. The temperature was raised to 40 ° C and stirred for 6 h. The temperature was lowered to 0 ° C and water was added to terminate the reaction. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The mixture was purified by preparative high performance liquid chromatography to obtain compound 317.4 mg (yield 9%), and 85.6 mg of the raw material compound B was recovered (recovery rate 57%).

[0030] 1 H NMR (600MHz, DMSO-d6) δ11.26(d,J=2.4Hz,1H,NH),11.18(s,J=2.6Hz,1H,NH),8.00(dd,J=8.2Hz,1.2Hz,2 H,ArH),7.63(t,J=7.4Hz,1H,ArH),7.51(t,J=7.4Hz,2H,ArH),7.45(d,J=2.5Hz,1H,ArH),7.44-7.42(m,2 H,ArH),7.37(d,J=7.9Hz,1H,ArH),7.34(d,J=8.5Hz,1H,ArH),7.11(td,J=7.4Hz,0.9Hz,1H,ArH),7.00(t d,J=7.4Hz,0.8Hz,1H,ArH),6.87(d,J=2.2Hz,1H,ArH),6.86(dd,J=8.7Hz,2.5Hz,1H,ArH),5.47(s,2H,-OC H2-CO-Ph),3.41(s,6H,2×OMe),3.33(s,6H,2×OMe); 13 C NMR (150MHz, DMSO-d6) δ195.6,151.8,147.6(2×C),147.4(2×C),135.9,134.6,133.6,131.4,128.8,127.9,127.3,127. 1,126.3,125.2,122.1,121.9,120.8,120.3,118.7,111.9,111.4(2×C),107.0,106.8,103.8,71.1,60.2(4×C); HRESIMS calcd for C 34 H 30 N2O6Na585.19961,found585.19861.

[0031] Example 4 Preparation of Compound 4

[0032] In a 25 mL two-necked reaction flask, compound B (150.0 mg, 0.3 mmol) was added and dissolved with 6 mL of N,N-dimethylformamide. Under argon protection, α-bromo-3,4-dichloroacetophenone (220.0 mg, 0.35 mmol) and KOH (58.0 mg, 1.04 mmol) were added. The temperature was raised to 40 ° C and stirred for 49 h. The reaction was terminated by cooling to 0 ° C and adding water. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The mixture was purified by preparative high performance liquid chromatography to obtain compound 417.4 mg (yield 8%), and compound B 90.6 mg (recovery rate 60%) was recovered.

[0033] 1 H NMR(600MHz,DMSO-d6)δ11.27(s,1H,NH),11.19(s,1H,NH),8.23(d,J=1.9Hz,1H,ArH), 7.96(dd,J=8.3,1.9Hz,1H,ArH),7.81(d,J=8.3Hz,1H,ArH),7.45(d,J=2.1Hz,1H,ArH) ,7.44-7.42(m,2H,ArH),7.37(d,J=7.9Hz,1H,ArH),7.34(d,J=8.7Hz,1H,ArH),7.11(t ,J=7.2Hz,1H,ArH),7.00(t,J=7.3Hz,1H,ArH),6.88-6.84(m,2H,ArH),5.49(s,2H,-OC H2 ),3.40(s,6H,2×OMe),3.35(s,6H,2×OMe); 13C NMR (150MHz, DMSO-d6) δ194.2,151.5,147.6(2×C),147.4(2×C),136.4,135.9,134.7,131.8,131.3,131.1,129.9,127.9,127.2 ,127.0,126.3,125.2,122.0,121.9,120.8,120.2,118.7,111.9,111.4,111.3,106.9,106.7,103.8,71.0,60.1(4×C); HRESIMS calcd forC 34 H 28 N2O6Cl2Na653.12166, found 653.11981.

[0034] Example 5 Preparation of Compound 5

[0035] In a 25 mL two-necked reaction flask, compound B (50.0 mg, 0.1 mmol) was added and dissolved with 2 mL of N,N-dimethylformamide. Under argon protection, bromoethane (75.0 μL, 1.0 mmol) and potassium carbonate (60 mg, 0.44 mmol) were added. The temperature was raised to 80°C and stirred for 30 h. After cooling to 0°C, water was added to terminate the reaction. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The mixture was purified by fast preparative liquid chromatography to obtain 513.6 mg of compound B (yield 25%), and 29.0 mg of compound B was recovered (recovery rate 58%).

[0036] 1 H NMR (600MHz, DMSO-d6) δ11.29(s,1H,NH),11.14(s,1H,NH),7.47(d,J=1.9Hz,1H,ArH),7.45-7.41(m,3H,ArH),7.32(d,J=8.7Hz,1H,ArH),7. 11(t,J=7.5Hz,1H,ArH),7.01(t,J=7.4Hz,1H,ArH),6.87(d,J=2.5Hz,1H,ArH),6.76(dd,J=8.7Hz,2.4Hz,1H,ArH),3.97(q,J=6.9Hz,2H,-OC H2 CH3),3.45(s,6H,2×OMe),3.43(s,6H,2×OMe),1.31(t,J=7.0Hz,3H); 13CNMR(150MHz,DMSO-d6)δ152.4,147.7(4×C),135.9,131.1,127.5,127.1,126.0,125.3,122.2,122 .1,120.8,120.3,118.7,112.0,111.5,111.4,107.0,106.8,103.0,63.3,60.3(4×C),14.9; HRESIMS calcd for C 28 H 28 N2O5Na 495.18904,found495.18777.

[0037] Example 6 Preparation of Compound 6

[0038] In a 25 mL two-necked reaction flask, compound B (50.0 mg, 0.1 mmol) was added and dissolved with 2.5 mL of N,N-dimethylformamide. Under argon protection, bromocyclopentane (34.0 μL, 0.32 mmol) and KOH (20.0 mg, 0.36 mmol) were added. The temperature was raised to 40°C and stirred for 10 h. The reaction was terminated by cooling to 0°C and adding water. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. After purification by a fast liquid preparative chromatography system, 618 mg of compound B (yield 31%) was obtained, and compound B (20 mg, recovery rate 40%) was recovered.

[0039] 1 H NMR(600MHz,DMSO-d6)δ11.28(s,1H,NH),11.13(s,1H,NH,),7.47(d,J=2.2H z,1H,ArH),7.46-7.41(m,3H,ArH),7.31(d,J=8.7Hz,1H,ArH),7.11(t,J=7.5 Hz,1H,ArH),7.00(t,J=7.4Hz,1H,ArH),6.88(d,J=2.4Hz,1H,ArH),6.74(dd,J=8.7,2.5Hz,1H,ArH),4.72(hept,J=5.9,2.9Hz,1H,cyclopentane-CH2CH2C H CH2CH2),3.45(s,6H,2×OMe),3.44(s,6H,2×OMe),1.86-1.50(m,8H,cyclopentane-C H2 C H2 CHC H2 C H2 ); 13C NMR(150MHz,DMSO-d6)δ151.2,147.7(2×C),147.6(2×C),135.9,131.0,127.4,127.1,126.0,125.2,122 .2,122.0,120.8,120.3,118.7,112.4,111.9,111.4,107.0,106.7,105.0,79.1(cyclopentane-CH2CH2 C HCH2CH2),60.3(4×C),32.3(2×C),23.6(2×C); HRESIMS calcdfor C 31 H 33 N2O5513.23840, found 513.23712.

[0040] Example 7 Preparation of Compound 7

[0041] In a 25 mL two-necked reaction flask, compound B (100.0 mg, 0.2 mmol) was added and dissolved with 4 mL of N,N-dimethylformamide. Under argon protection, 2-(4-)morpholinoethyl bromide (72.0 μL, 0.5 mmol) and KOH (24.0 mg, 0.43 mmol) were added. The temperature was raised to 40 ° C and stirred for 24 h. The reaction was terminated by cooling to 0 ° C and adding water. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. After preparation by preparative high performance liquid chromatography, 748 mg of compound B was obtained (yield 38%), and 32 mg of compound B was recovered (recovery rate 32%).

[0042] 1 H NMR (600MHz, DMSO-d6) δ11.34(d,J=1.6Hz,1H,NH),11.27(d,J=2.0Hz,1H,NH),7.48-7.44(m,3H,ArH),7.42(d,J=7.9Hz,1H,ArH),7.38(d,J=8.7H z,1H,ArH),7.12(t,J=7.4,1H,ArH),7.01(t,J=7.4,1H,ArH),6.98(d,J=2.4Hz,1H,ArH),6.87(dd,J=8.8,2.4Hz,1H,ArH),4.31(t,J=4.9,2H,-OC H2 -CH2-morpholine),4.00-3.68(m,4H,morpholine-N(CH2C H2 )2O),3.56-3.52(m,4H,morpholine-N(C H2CH2)2O),3.46(s,6H,2×OMe),3.43(s,6H,2×OMe),3.22(brs,2H,-O-CH2-C H2 -morpholine); 13 C NMR(150MHz,DMSO-d6)δ151.4,147.7(2×C),147.6(2×C),135.9,131.6,127.4,127.0,126.4,125.3,122.2,122.0,12 0.8,120.3,118.7,112.1,111.4,111.3,106.9(2×C),104.0,63.3(2×C),62.8,60.3(4×C),55.4,51.8(2×C); HRESIMS calcd for C 32 H 36 N3O6 558.25986,found558.25940.

[0043] Example 8 Preparation of Compound 8

[0044] In a 25 mL two-necked reaction flask, glucose penta-O acetate (1.0 g, 2.56 mmol) was added and dissolved with 10 mL of dichloromethane. Under argon protection, bromoethanol (384.0 μL, 3.12 mmol) was added, and boron trifluoride-ether (1.60 mL, 11.63 mmol) was added at -20°C. After stirring at 0°C for 1 h, the reaction was transferred to room temperature for 13 h, cooled to 0°C, and water was added to terminate the reaction. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The mixture was chromatographed on a silica gel column with an eluent of petroleum ether: ethyl acetate 5:1 to obtain 1.35 g (yield 90%) of compound 1-(2-bromoethoxy)-2,3,4,6-tetraacetyl glucose.

[0045] 1 H NMR(600MHz,DMSO-d6)δ5.26(t,J=9.6Hz,1H,C3-H),4.91(t,J=9.6Hz,1H,C4-H),4.87(d,J=8.0Hz,1H,C 1-H),4.79(dd,J=9.7,8.1Hz,1H,C2-H),4.19-4.16 / 4.05-4.01(m,2H,Glc-C6-H),4.02-3.97(m,2H,-OC H2 CH2Br),3.82-3.78(m,1H,C5-H),3.63-3.53(m,2H,-OCH2C H2 Br),2.02(s,3H,-COC H3 ),2.01(s,3H,COCH3 ),1.98(s,3H,COC H3 ),1.94(s,3H,COCH3); 13 C NMR (150MHz, DMSO-d6) δ170.0,169.5,169.3,169.0,99.3,72.0,70.7(2×C),69.1,68.1,61.7,31.8,20.5,20.5,20.4,20.3.

[0046] In a 25 mL two-necked reaction flask, compound B (100.0 mg, 0.2 mmol) was added and dissolved with 6 mL of N,N-dimethylformamide. Under argon protection, 1-(2-bromoethoxy)-2,3,4,6-tetraacetyl glucose (288.0 mg, 0.6 mmol) and KOH (42.0 mg, 0.75 mmol) were added. The temperature was raised to 40 ° C. and stirred for 22 h. The temperature was lowered to 0 ° C. and water was added to terminate the reaction. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. After preparation by preparative high performance liquid chromatography, 829.8 mg of 2,3,4,6-tetraacetyl compound (yield 16%) was obtained, and 45.8 mg of compound B (recovery rate 46%) was recovered.

[0047] 1 H NMR (600MHz, DMSO-d6) δ11.28(d,J=2.5Hz,1H,NH),11.15(d,J=2.5Hz,1H,NH),7.46(d,J=2.5Hz,1H,ArH),7.44(d,J=8.1Hz,ArH,1H),7.4 3-7.40(m,2H,ArH),7.33(d,J=8.8Hz,1H,ArH),7.11(td,J=7.6Hz,1.1Hz,1H,ArH),7.00(td,J=7.5Hz,0.9Hz,1H,ArH),6.86(d,J=2.4Hz, 1H, ArH), 6.79 (dd, J=8.7, 2.4Hz, 1H, ArH), 5.26 (t, J=9.6Hz, 1H, Glc-C3-H), 4.91 (d, J=8.0Hz, 1H, Glc-C4-H), 4.89 (t, J=9.6Hz, 1H, Glc-C 1-H),4.78(dd,J=9.8,8.0Hz,1H,Glc-C2-H),4.17(dd,J=12.4,5.1Hz,1H,Glc-C6-H),4.08-4.04(m,1H,Glc-C6-H),4.02-3.98(m,4H,-OC H2 C H2O-),3.87-3.83(m,1H,Glc-C5-H),3.44(s,6H,2×OMe),3.43(s,6H,2×OMe),1.98(s,3H,COC H3 ),1.97(s,3H,COC H3 ),1.92(s,3H,COC H3 ),1.87(s,3H,COC H3 ); 13 C NMR(150MHz,DMSO-d6)δ170.1,169.6,169.3,169.1,152.2,147.6(4×C),135.9,131.2,127.5,127.1,126.1,125.2,122.2,122.1,120.8,120.3 ,118.7,112.0,111.4,111.3,107.0,106.8,103.2,99.7,72.1,70.9,70 .6,68.2,68.1,67.3,61.7,60.3(4×C),20.5,20.4,20.3(2×C); HRESIMS calcd for C 42 H 47 N2O 15 819.29710,found819.29742.

[0048] In a 10 mL single-necked reaction bottle, 2,3,4,6-tetraacetyl compound 8 (15.0 mg, 0.018 mmol) was added and dissolved in 5 mL of methanol. Sodium methoxide / methanol solution with a pH of 14 was added dropwise at room temperature and the pH was adjusted to 9. After 15 minutes, cationic resin was added and adjusted to neutral. The mixture was filtered and the product 811.5 mg (yield 94%) was prepared by fast preparative liquid chromatography system.

[0049] 1 H NMR(600MHz,DMSO-d6)δ11.29(s,1H,NH),11.16(s,1H,NH),7.46(d,J=2.5Hz,1H ,ArH),7.45-7.41(m,3H,ArH),7.33(d,J=8.7Hz,1H,ArH),7.11(t,J=7.5Hz,1H, ArH),7.00(t,J=7.4Hz,1H,ArH),6.87(d,J=2.4Hz,1H,ArH),6.80(dd,J=8.7,2. 4Hz,1H,ArH),4.22(d,J=7.8Hz,1H,Glc-C1-H),4.17-4.04 / 3.83-3.77(m,4H,-OC H2 CH2 O-),3.44(s,6H,2×OMe),3.43(s,6H,2×OMe),3.68-3.64 / 3.17-2.96(m,6H,Glc-2 / 3 / 4 / 5 / 6-H); 13 C NMR(150MHz,DMSO-d6)δ152.3,147.7(4×C),135.9,131.2,127.5,127.1,126.0,125.3,122.2,122.1,120.8,120.3,1 18.7,112.0,111.4,111.3,107.0,106.8,103.2,103.1,76.9,76.7,73.4,70.1,67.5,67.3,61.1,60.34×C); HRESIMS calcd for C 34 H 38 N2O 11 Na673.23678,found 673.23621.

[0050] In order to further verify the beneficial effects of the compounds of the present invention, the anti-tumor activity of the compounds synthesized in Examples 1-8 was tested. The specific experiments are as follows:

[0051] Preparation of test sample solution: The test samples are compounds 1 to 8 synthesized in Examples 1 to 8 above. Accurately weigh an appropriate amount of sample and prepare a solution of the desired concentration with DMSO for activity testing.

[0052] Cell lines and cell subculture: MV4-11 and L-02 cells were used for activity testing. Cells were prepared into a single cell suspension using culture medium containing 10% fetal bovine serum, and 5×10 cells were inoculated into each well of a 96-well plate in 100 μL. 4 The cells were pre-cultured at 5% CO2 and 37°C for 24 h.

[0053] This experiment uses the Cell Counting Kit-8 (CCK-8) method to detect the inhibitory effect of different drugs on tumor cell growth. In the activity test, MV4-11 and L-02 cells in the logarithmic growth phase were taken and cultured with 10% fetal bovine serum to a density of 5×10 per ml. 4After counting, cells were inoculated into 96-well culture plates at a density of 5,000 cells / 100 μL / well. 100 μL of drug solution was added to each well and cultured for 48 hours. The old culture medium was aspirated and 100 μL of CCK-8 solution diluted tenfold was added directly to each well. The cells were cultured for 2-3 hours at 37°C and 5% CO2. The absorbance at 450 nm was measured using a microplate reader. The cell viability (%) was calculated according to the following formula: IR% = (Oddrug-Odblank) / ODcountrol-Odblank)*100%. The IC value of the sample was calculated using GraphPad Prism 8 software. 50 value.

[0054] Positive control sample: PKC-412.

[0055] Table 1. Inhibitory activity of compounds 1 to 8 on human leukemia cell proliferation (IC 50 )

[0056]

[0057] a Selectivity Index (SI) = IC 50 L-02 / IC 50 MV4-11

[0058] As shown in Table 1, compounds 1 to 8 have strong inhibitory activity against human leukemia MV4-11 cell line, but have weak inhibitory effects on human normal liver cell L-02. 50 The selectivity of compounds 5 and 6 was higher than that of the marketed drug PKC-412, indicating that all the compounds of the present invention had a highly selective inhibitory effect on the human leukemia cell line MV4-11 relative to normal human liver cells L-02.

[0059] The above embodiments are merely examples for clarity of explanation and are not intended to limit the embodiments. Those skilled in the art will appreciate that other variations or modifications based on the above descriptions are possible. It is not necessary and impossible to enumerate all embodiments here. Obvious variations or modifications arising therefrom remain within the scope of protection of the present invention.

Claims

1. A bisindole biphenyl compound, characterized in that: The compound structural formula is any one of formulas 1-8:

2. A use of the bisindole biphenyl compound according to claim 1, characterized in that: The bisindolebiphenyl compound is used for preparing medicine for preventing or treating acute myeloid leukemia.

3. The use of the bisindole biphenyl compound according to claim 2, characterized in that: The bisindole biphenyl compound is used for preparing a drug for resisting leukemia formed by a human leukemia cell line MV4-11.

4. The use of the bisindole biphenyl compound according to claim 2, wherein: When the compound is used as medicine, it can be used directly or in the form of a pharmaceutical composition. The pharmaceutical composition contains 0.1-99% of the compound, and the rest is a pharmaceutical carrier.

5. A drug for preventing or treating acute myeloid leukemia, characterized in that: The medicine comprises the compound according to claim 1 and a pharmaceutically acceptable carrier.

6. The drug for preventing or treating acute myeloid leukemia according to claim 5, characterized in that: The pharmaceutically acceptable carrier is one or more solid, semi-solid and liquid diluents, fillers and pharmaceutical product adjuvants, including fillers, diluents, emulsifiers, disintegrants, binders and drug-carrying carriers without toxic side effects.

7. The drug for preventing or treating acute myeloid leukemia according to claim 5, characterized in that: The dosage forms of the medicine are tablets, injections, capsules and granules.

Images