Brucea javanica bitter alcohol triphenylphosphine derivative as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a triphenylphosphine brucea javanica bitter alcohol derivative with anti-tumor activity in dry fruits of a medicinal plant brucea javanica, and a preparation method and application of the triphenylphosphine brucea javanica bitter alcohol derivative. According to the invention, a series of brucea javanica triphenylphosphine derivatives or pharmaceutically acceptable salts thereof are designed and synthesized by carrying out necessary structural modification on brucea javanica. Anti-tumor drug screening on digestive system cancer cell proliferation through pharmacological experiments shows that the brucea javanica bitter alcohol derivative or the pharmaceutically acceptable salt thereof has good gastric cancer cell inhibition activity, so that the brucea javanica bitter alcohol derivative or the pharmaceutically acceptable salt thereof can be developed into new anti-gastric cancer drugs and has very high potential research value and clinical application prospect.

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and specifically relates to a preparation method and use of brucea brucea in Brucea javanica, and in particular to a triphenylphosphine brucea brucea derivative with anti-tumor activity in the dried fruit of the medicinal plant Brucea javanica, and a preparation method and use thereof. Background Art

[0002] Currently, mitochondria have attracted attention as emerging pharmacological targets because mitochondria play a key role in many important physiological functions and their damage plays a decisive role in the development of many diseases. Triphenylphosphine (TPP), as the most widely used lipophilic cationic ligand targeting mitochondria, is composed of a positively charged phosphorus ion connected to three benzene rings. Its high lipid solubility is guaranteed by the spatial closure of the benzene rings, and the positive charge on the phosphorus atom can be delocalized to the three benzene rings to form a delocalized positive charge, which promotes TPP to pass through the lipid bilayer and target the interior of the mitochondria.

[0003] Bruce ajavanica (L.) Merr. is a plant of the genus Brucea in the family Simulaceae. Brucea ajavanica is used as medicine with its fruit and leaves, and is a commonly used Chinese medicine. Brucea ajavanica is cold in nature and bitter in taste. It belongs to the large intestine meridian and the liver meridian. It has the effects of clearing away heat and detoxifying, stopping malaria, stopping dysentery, and corroding warts. Studies have shown that quasin compounds are the main components of Brucea ajavanica. This type of compound includes an unsaturated six-membered ring (marked as A), two cyclohexane rings (marked as B and C), a six-membered lactone ring (marked as D), and a tetrahydrofuran ring (marked as E). In its molecular structure, hydroxyl groups usually exist at positions C-3, 11, 12, and 15, and the hydroxyl group at position 15 often appears in the form of an ester. Among them, brucea brucea picroside is a quasin compound with a relatively high content (content of about 0.3%) and a stable source.

[0004]

[0005] Brucea brucea has significant biological activity, and semi-synthetic modification using this compound as a starting material has broad application prospects in the pharmaceutical industry. The inventors have synthesized a series of brucea brucea derivatives based on tumor mitochondrial targeting design ideas by researching literature and using brucea brucea as the parent nucleus. Summary of the invention

[0006] In order to solve the above technical problems, the present invention uses brucein as the mother nucleus to prepare a series of tumor mitochondrial targeting derivatives or pharmaceutically acceptable salts thereof, and further provides a pharmaceutical composition comprising the derivative or pharmaceutically acceptable salt thereof, and a method for preparing the derivative or pharmaceutically acceptable salt thereof. In addition, the present invention also provides the use of the derivative or pharmaceutically acceptable salt thereof or pharmaceutical composition thereof in the preparation of a drug targeting digestive system tumors.

[0007] Specifically, the present invention is realized through the following technical solutions:

[0008] In a first aspect, the present invention provides a brucein triphenylphosphine derivative having anti-digestive system tumor activity or a pharmaceutically acceptable salt thereof, wherein the brucein triphenylphosphine derivative has a chemical structure of formula (I),

[0009]

[0010] R in formula (I) is selected from:

[0011]

[0012] More preferably, R in formula (I) is selected from:

[0013] More preferably, the brucein triphenylphosphine derivative or its pharmaceutically acceptable salt having anti-digestive system tumor properties is selected from the following:

[0014]

[0015]

[0016] In a second aspect, the present invention provides a pharmaceutical composition comprising the brucein triphenylphosphine derivative or a pharmaceutically acceptable salt thereof as described in the first aspect, and a pharmaceutically acceptable carrier.

[0017] The dosage form of the pharmaceutical composition is an oral dosage form or an injection dosage form, wherein the oral dosage form is a capsule, a tablet, a granule, an oral liquid, a sustained-release preparation or a controlled-release preparation.

[0018] Preferably, the pharmaceutically acceptable carrier is selected from one or more of a diluent, a lubricant, a binder, a disintegrant, a stabilizer or a solvent.

[0019] More preferably, the diluent of the present invention is selected from starch, microcrystalline cellulose, sucrose, dextrin, lactose, powdered sugar, glucose; the lubricant is selected from magnesium stearate, stearic acid, sodium chloride, sodium oleate, sodium lauryl sulfate, poloxamer; the binder is selected from water, ethanol, starch slurry, syrup, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, sodium alginate, polyvinyl pyrrolidone; the disintegrant is selected from starch effervescent mixture, i.e. sodium bicarbonate and citric acid, tartaric acid, low-substituted hydroxypropyl cellulose; the stabilizer is selected from polysaccharides such as acacia gum, agar, alginic acid, cellulose ether and carboxymethyl chitosan; the solvent is selected from water and a balanced salt solution.

[0020] In a third aspect, the present invention provides a method for preparing the brucein triphenylphosphine derivative or a pharmaceutically acceptable salt thereof as described in the first aspect, the preparation method comprising the following steps:

[0021]

[0022]

[0023] Using brucea stearoyl alcohol (BST) as the starting material, compound BP-1-3 is prepared through step a, compound BP-4 is prepared through step b, and compound BP-5-7 is prepared through steps c and d;

[0024] Specifically, the preparation method comprises the following steps:

[0025] (1) Synthesis of BP-1-3 and BST-6C: Dissolve BST, EDCI and DMAP in a solvent, stir at room temperature, add the corresponding carboxylic acid fragment, and react at room temperature. Remove the solvent, extract, wash, dry, filter and purify;

[0026] (2) Synthesis of BP-4: Weigh 10-bromodecanoic acid and triphenylphosphine, dissolve in a solvent, and reflux to react. Obtain intermediate 1. Similar to the synthesis of BP-1, dissolve BST, EDCI and DMAP in a solvent, stir at room temperature, add intermediate 1, and react at room temperature; post-treatment is the same as step (1);

[0027] (3) Synthesis of BP-5-7: Dissolve BST-6C and the corresponding triphenylphosphine in a solvent, react at room temperature, and perform post-treatment in the same manner as step (1).

[0028] The above preparation method, wherein:

[0029] The solvent is anhydrous acetonitrile, anhydrous acetone, N,N-dimethylformamide, tetrahydrofuran or dichloromethane;

[0030] The acid binding agent is triethylamine, N,N-diisopropylethylamine, pyridine or 4-dimethylaminopyridine;

[0031] The condensing agent is dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI).

[0032] In a fourth aspect, the present invention provides use of the brucea bruceiol triphenylphosphine derivative or a pharmaceutically acceptable salt thereof as described in the first aspect, or the pharmaceutical composition as described in the second aspect, in the preparation of drugs for treating digestive system tumors.

[0033] Preferably, the digestive system tumor is gastric cancer, colon cancer or liver cancer.

[0034] Compared with the prior art, the present invention has the following beneficial effects:

[0035] The present invention designs and synthesizes a series of novel brucein derivatives or pharmaceutically acceptable salts thereof by making necessary structural modifications to brucein. Through pharmacological experiments, anti-tumor drug screening for the proliferation of digestive system cancer cells is conducted and it is found that the brucein derivatives or pharmaceutically acceptable salts thereof of the present invention have good gastric cancer cell inhibition activity, and thus can be developed into new anti-gastric cancer drugs, which have very high potential research value and clinical application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 : The inhibitory activity of the brucea javanica triphenylphosphine derivative prepared by the present invention on HepG2, MGC-803, HCT116 and L-02 cells. DETAILED DESCRIPTION

[0037] The present invention is further described below with reference to specific embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the scope of the present invention. If specific techniques or conditions are not specified in the embodiments, they are carried out according to the techniques or conditions described in the literature in this field, or according to the product instructions. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased through regular channels.

[0038] Example 1: Preparation of compound BP-1:

[0039]

[0040] Take a 10mL reaction bottle, dissolve BST (20.0mg, 38.42μmol, 1eq) in 2mL dry DCM, add EDCI (11.05mg, 57.63μmol, 1.5eq), DMAP (18.78mg, 153.69μmol, 4eq) and (3-propylcarboxyl) triphenylphosphonium bromide (19.15mg, 46.11μmol, 1.2eq) and react at 25℃ for 12h. TLC monitors the completion of the reaction, add 2mL dry DCM to the reaction solution, extract twice with 5mL saturated ammonium chloride aqueous solution, extract once with 5mL saturated sodium chloride aqueous solution, collect the organic phase, dry over anhydrous sodium sulfate, remove the solvent under reduced pressure, and purify by RP-HPLC to obtain BP-1: white solid, the structural identification data are as follows:

[0041] BP-1: 1H NMR(600MHz,Chloroform-d)δ7.83-7.73(overlap,10H),7.70-7.65(overlap,5H),6.16(s,1 H),5.62(s,1H),4.82(s,1H),4.69(d,J=7.8Hz,1H),4.30(d,J=6.3Hz,2H),3.92-3.84(m,2H), 3.72(m,4H),3.20(s,1H),3.01-2.89(m,4H),2.34-2.26(m,2H),2.13(d,J=1.3Hz,3H),2.06( d,J=3.8Hz,1H),1.88(d,J=1.3Hz,3H),1.83-1.80(m,1H),1.76(d,J=1.4Hz,3H),1.42(s,3H); 13 C NMR(150MHz,Chloroform-d)δ189.8,171.2,170.7,167.7,165.0,159.8,146.8 ,142.0,135.2,135.2,135.1,133.8×3,133.7×3,130.7×3,130.6×3,118.5,118 .3,117.7,114.7,82.6,81.6,75.7,73.3,71.0,66.6,52.8,51.8,49.9,45.3,4 3.0,41.3,40.8,33.4,29.7,27.6,20.6,18.6,15.5,14.8; HR-ESI-MS:m / zcalcd for C 47 H 50 O 12 P[M-Br] + 837.3034, found 837.3057.

[0042] Example 2: Preparation of compound BP-2:

[0043]

[0044] The preparation method of BP-2 is the same as above, and the structural identification data are as follows:

[0045] BP-2: white solid, 1H NMR(600MHz,Chloroform-d)δ7.81-7.65(overlap,15H),6.14(s,1H),5.64(s,1H) ,4.84(s,1H),4.72(d,J=7.6Hz,1H),4.40(s,2H),3.71(m,4H),3.25(s,1H),2.98-2 .91(m,2H),2.62-2.59(m,2H),2.40(s,1H),2.32-2.25(m,3H),2.16(d,J=1.3Hz,3H ),2.07(s,1H),1.90(d,J=1.3Hz,3H),1.85-1.78(m,3H),1.72(s,3H),1.43(s,3H); 13 C NMR(150MHz,Chloroform-d)δ189.5,173.8,171.3,167.7,165.0,160.1,146.1,142.2,135.3,135.3,135.1,133.9×6,130.5×6,118.7,118.5,117.9 ,114.7,82.6,81.7,75.9,73.9,71.0,66.6,52.9,51.6,50.0,45.4,43.0, 41.4,40.9,32.8,29.8,27.7,21.5,20.6,15.5,14.7,14.2; HR-ESI-MS:m / z calcd for C 48 H 52 O 12 P[M-Br] + 851.3191, found851.3162.

[0046] Example 3: Preparation of compound BP-3:

[0047]

[0048] The preparation method of BP-3 is the same as above, and the structural identification data are as follows:

[0049] BP-3: white solid, 1H NMR(600MHz,Chloroform-d)δ7.84-7.70(overlap,15H),6.20(s,1H),5.64(s,1H),4.83(s,1H) ,4.73(d,J=7.8Hz,1H),4.36-4.27(m,2H),3.75(s,4H),3.66(h,J=6.4Hz,2H),3.20(s,1H),2.9 9(d,J=12.5Hz,1H),2.95(d,J=16.2Hz,1H),2.50-2.44(m,2H),2.37-2.25(m,2H),2.17(d,J=1. 3Hz,3H),2.07(s,1H),1.91(d,J=1.3Hz,3H),1.85-1.74(m,6H),1.71-1.67(m,2H),1.46(s,3H); 13 C NMR (150MHz, Chloroform-d) δ189.6,171.7,171.4,167.5,164.9,160.4,146.0,142.3,135.3×3,130.74×6,130.74×6,118.6×1,118.3,114.5,82 .6,81.6,75.9,73.7,70.9,66.3,53.0,51.0,50.2,45.4,43.0,41.6,40 .9,29.0,27.8,24.3,22.8,22.4,22.3,20.7,15.6,14.7; HR-ESI-MS:m / z calcd for C 49 H 54 O 12 P[M-Br] + 865.3347, found 865.3368.

[0050] Example 4: Preparation of compound BP-4:

[0051]

[0052] Accurately weigh the reactant 10-bromodecanoic acid (23.94 mg, 95.31 μmol, 1 eq) and place it in a 100 mL eggplant-shaped bottle, then accurately weigh another reactant triphenylphosphine (50.0 mg, 190.63 μmol, 2 eq) and add it to the eggplant-shaped bottle, then add 5 mL of anhydrous acetonitrile as a solvent, dissolve the mixture in the acetonitrile solvent, and reflux and stir at 80 ° C for 12 hours under nitrogen protection. After the reaction is completed, the crude product is purified by preparative thin layer, the effective component is extracted with dichloromethane, and then excess water is removed with anhydrous sodium sulfate to obtain the intermediate (6-hexylcarboxyl) triphenylphosphonium bromide.

[0053] Take a 10mL reaction bottle, dissolve BST (20.0mg, 38.42μmol, 1eq) in 2mL dry DCM, add EDCI (11.05mg, 57.63μmol, 1.5eq), DMAP (18.78mg, 153.69μmol, 4eq) and (3-propylcarboxyl) triphenylphosphonium bromide (23.67mg, 46.11μmol, 1.2eq) and react at 25℃ for 12h. TLC monitors the completion of the reaction, adds 2mL dry DCM to the reaction solution, extracts twice with 5mL saturated ammonium chloride aqueous solution, extracts once with 5mL saturated sodium chloride aqueous solution, collects the organic phase, and removes the solvent under reduced pressure after drying with anhydrous sodium sulfate. Purify by RP-HPLC to obtain BP-4: white solid, the structural identification data are as follows:

[0054] BP-4: 1 H NMR(600MHz,Chloroform-d)δ7.86-7.67(overlap,15H),6.22(s,1H),5.64(s,1H),4.83(s,1H),4.73( d,J=7.8Hz,1H),4.33(d,J=4.6Hz,1H),4.29(s,1H),3.76(s,4H),3.71(dd,J=13.0,8.5Hz,2H),3.18(s, 1H),3.01-2.94(m,2H),2.49(q,J=6.9Hz,2H),2.38-2.27(m,2H),2.18(d,J=1.3Hz,3H),2.07(s,1H),1. 92(d,J=1.3Hz,3H),1.85-1.82(m,1H),1.82-1.78(m,2H),1.77(s,3H),1.73-1.67(m,4H),1.47(s,3H); 13 C NMR (150MHz, Chloroform-d) δ189.5,171.8,171.5,167.4,164.9,160.6,145.9,142.3,135.3×2,133.8×6,130.7×6,118.7×2,118.1,115.1,82.5, 81.6,75.9,73.8,71.9,66.5,53.1,51.1,50.2,45.4,43.0,41.7,40.9,2 9.5,29.5,27.8,24.4,22.9,22.6,22.4,20.7,15.6,14.7; HR-ESI-MS:m / z calcd for C 50 H 56 O 12 P[M-Br]+ 879.3504, found 879.3511.

[0055] Example 5: Preparation of compound BP-5:

[0056]

[0057] Take a 10mL reaction bottle, dissolve BST (20.0mg, 38.42μmol, 1eq) in 2mL dry DCM, add EDCI (11.05mg, 57.63μmol, 1.5eq), DMAP (18.78mg, 153.69μmol, 4eq) and 6-bromo-hexanoic acid (8.99mg, 46.11μmol, 1.2eq) and react at 25°C for 12h. TLC monitors the completion of the reaction, adds 2mL dry DCM to the reaction solution, extracts twice with 5mL saturated ammonium chloride aqueous solution, extracts once with 5mL saturated sodium chloride aqueous solution, collects the organic phase, dries with anhydrous sodium sulfate, removes the solvent under reduced pressure, and purifies with RP-HPLC to obtain BST-6C.

[0058] Accurately weigh the reactant BST-6C (20.00 mg, 28.67 μmol, 1 eq) and place it in a 10 mL eggplant-shaped bottle. Then accurately weigh another reactant triphenylphosphine (37.60 mg, 143.35 μmol, 5 eq) and add it to the eggplant-shaped bottle. Then add 2 mL of anhydrous acetonitrile as a solvent, dissolve the mixture in the acetonitrile solvent, and reflux and stir at 80 ° C for 12 hours under nitrogen protection. After the reaction is completed, the crude product is purified by preparative thin layer, the effective component is extracted with dichloromethane, and then excess water is removed with anhydrous sodium sulfate to obtain BP-5: a white solid, the structural identification data are as follows:

[0059] BP-5: 1 H NMR(600MHz,Chloroform-d)δ7.70-7.62(overlap,6H),7.48(overlap,6H),6.20(s,1H),5.65(s,1H),4.84(s,1H),4.73(d,J=7.8Hz,1H),4.33(m 2H),3.75(s,4H),3.60(s,2H),3.30(s,1H),3.02-2.97(m,2H),2.46(s,9H),2.36-2.25(m,2H),2.17(d,J=1. 3Hz,3H),2.07(s,1H),1.91(d,J=1.3Hz,3H),1.86-1.81(m,3H)1.75(s,3H),1.73-1.59(m,6H),1.47(s,3H); 13C NMR(150MHz,Chloroform-d)δ189.5,174.2,171.4,167.4,164.7,160.2,146.2,146.2,1 46.0,146.0,142.2,133.6,133.6×2,133.5×2,131.3×2,131.2×2,131.1×2,115.7,115.5 ,115.1,114.5,82.5,81.5,75.8,73.6,70.8,66.2,52.8,51.5,50.1,45.3,42.9,41.6,4 0.8,33.5,29.7,28.9,27.6,24.5,24.3,22.9,21.9×2,20.6,15.5,14.6; HR-ESI-MS:m / z calcd for C 53 H 62 O 12 P[M-Br] + 921.3973, found 921.3953.

[0060] Example 6: Preparation of Compound BP-6:

[0061]

[0062] Accurately weigh the reactant BST-6C (20.00 mg, 28.67 μmol, 1 eq) and place it in a 10 mL eggplant-shaped bottle. Then accurately weigh another reactant triphenylphosphine (45.34 mg, 143.35 μmol, 5 eq) and add it to the eggplant-shaped bottle. Then add 2 mL of anhydrous acetonitrile as a solvent, dissolve the mixture in the acetonitrile solvent, and reflux and stir at 80 ° C for 12 hours under nitrogen protection. After the reaction is completed, the crude product is purified by preparative thin layer, the effective component is extracted with dichloromethane, and then excess water is removed with anhydrous sodium sulfate to obtain BP-6: a white solid, the structural identification data are as follows:

[0063] BP-6: 1H NMR(600MHz,Chloroform-d)δ7.97-7.86(overlap,6H),7.46-7.38(overlap,6H),6.15(s,1 H),5.63(s,1H),4.83(s,1H),4.71(d,J=7.7Hz,1H),4.39-4.27(m,2H),3.75(m,4H),3.60(s, 2H),3.22(s,1H),2.96(m,2H),2.50-2.38(m,2H),2.35-2.24(m,2H),2.16(s,3H),2.09-2.04 (m,1H),1.98(s,2H),1.91(s,3H),1.84-1.79(m,1H),1.74(s,3H),1.67(s,4H),1.43(s,3H); 13 C NMR(150MHz,Chloroform-d)δ189.5,174.0,171.3,167.6,166.6×3(d,J=244.5Hz),165.8,160 .2,145.9,142.1,136.8,136.7,136.6,118.5×3(d,J=3.33Hz),114.5,114.3(d,J=9.0Hz),114 .3(d,J=9.0Hz),113.7(d,J=9.0Hz),82.5,81.5,75.8,73.5,70.8,66.2,52.8,51.5,50.0,45. 3,42.9,41.4,40.8,33.4,29.7,28.9,27.6,24.3,24.2,22.9,20.5,15.4,14.6; HR-ESI-MS:m / z calcd for C 50 H 53 O 12 F3P[M-Br] + 933.3221, found 933.3204.

[0064] Example 7: Preparation of Compound BP-7

[0065]

[0066] The preparation method of BP-7 is the same as above, and the structural identification data are as follows:

[0067] BP-7: white solid, 1H NMR(600MHz,Chloroform-d)δ7.70-7.62(overlap,6H),7.48(overlap,6H),6.20(s,1H),5.65(s,1H),4.84(s,1H),4.73(d,J=7.8Hz,1H),4.33(m 2H),3.75(s,4H),3.60(s,2H),3.30(s,1H),3.02-2.97(m,2H),2.46(s,9H),2.36-2.25(m,2H),2.17(d,J=1. 3Hz,3H),2.07(s,1H),1.91(d,J=1.3Hz,3H),1.86-1.81(m,3H)1.75(s,3H),1.73-1.59(m,6H),1.47(s,3H); 13 C NMR(150MHz,Chloroform-d)δ189.5,174.2,171.4,167.4,164.7,160.2,146.2,146.2,1 46.0,146.0,142.2,133.6,133.6×2,133.5×2,131.3×2,131.2×2,131.1×2,115.7,115.5 ,115.1,114.5,82.5,81.5,75.8,73.6,70.8,66.2,52.8,51.5,50.1,45.3,42.9,41.6,4 0.8,33.5,29.7,28.9,27.6,24.5,24.3,22.9,21.9×2,20.6,15.5,14.6; HR-ESI-MS:m / z calcd for C 53 H 62 O 12 P[M-Br] + 921.3973, found 921.3953.

[0068] Example 8: Anti-tumor activity screening

[0069] Cell lines: Human hepatoma HepG2, gastric cancer MGC-803, colon cancer HCT116 and human normal liver cells L-02 were purchased from American Type Culture Collection (ATCC, Rockville, MD, USA). Cells were inoculated in DMEM culture medium containing 10% fetal bovine serum, 10 mg / mL streptomycin, 100 U / mL penicillin and 0.03% glutamine. The culture environment was 37°C and a humidified atmosphere of 5% carbon dioxide.

[0070] Instruments: carbon dioxide incubator (Thermo, USA); 96-well culture plate (NestBiotech, USA); microplate reader (BIO-RAD Model 680, Thermo, USA).

[0071] Reagents: Trypsin (Biological Industries, USA); fetal bovine serum (Biological Industries, USA); DMEM medium (HyClon, USA); methylthiazolyl blue (MTT, Sigma, USA); DMSO (Sigma, USA).

[0072] Drugs and their concentration gradients: the concentration gradients of BP-1-7 and bruceiol (BST) are 10, 1, 0.1, 0.05, 0.01 μM; the concentration gradient of sorafenib (SORA) is 91.9416, 81.8098, 62.0682, 14.0786, 5.678, 1.6476 μM; the concentration gradient of doxorubicin (DOX) is 88.1056, 87.6575, 62.4854, 34.3811, 22.5354, 0.168 μM; the concentration gradient of oxaliplatin (OXA) is 62.5515, 55.1225, 45.3497, 31.1502, 12.619, 8.147 μM;

[0073] Experimental method: The cytotoxicity of the above drugs on MGC-803, HepG2, HCT116 and L-02 cells was determined by MTT method. 3 Cells were seeded at a density of 100 cells / well in a 96-well plate and cultured overnight. Then, cells were treated with different concentrations of the above compounds or dimethyl sulfoxide for 24, 48, and 72 h, and 20 μL of MTT (5 mg / mL) was added to each well and incubated for 4 h. After removing the culture medium, 150 μL of dimethyl sulfoxide was added to the wells, and the results were obtained using a microplate reader (Thermo, Carlsbad, CA, USA) at 490 nm. The experiment was repeated 3 times, and the IC was calculated using GraphPad Prism 6 software. 50 value.

[0074] Calculation formula:

[0075] Cell growth inhibition rate (%) = (A 490(control) -A 490(druggroups )) / (A 490(control) -A 490(blank) )×100%

[0076] Filter results such as Figure 1 shown.

[0077] In these tests, it was found that the selectivity index (SI value) of fluorine-substituted BP-6 for gastric cancer cell MGC-803 was as high as 49.0, which far exceeded that of BP-5 (SI=7.5) and BST (SI=1.38).

[0078] Although the specific embodiments of the present invention have been described in detail, according to all the teachings disclosed, those skilled in the art can make various modifications and substitutions to the details of the technical solution of the present invention, and these changes are within the protection scope of the present invention. The full protection scope of the present invention is given by the attached claims and any equivalents thereof.

Claims

1. A brucein triphenylphosphine derivative or a pharmaceutically acceptable salt thereof having anti-digestive system tumor activity, characterized in that: The brucea brucea triphenylphosphine derivative has a chemical structure of formula (I): R in formula (I) is selected from:

2. The brucein triphenylphosphine derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: R in formula (I) is selected from:

3. The brucein triphenylphosphine derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The brucein triphenylphosphine derivative is selected from the following:

4. A pharmaceutical composition, characterized in that: The pharmaceutical composition comprises the brucein triphenylphosphine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, and a pharmaceutically acceptable carrier.

5. The pharmaceutical composition according to claim 4, characterized in that: The dosage form of the pharmaceutical composition is an oral dosage form or an injection dosage form, the oral dosage form is a capsule, a tablet, a granule, an oral liquid, a sustained-release preparation or a controlled-release preparation, and the pharmaceutically acceptable carrier is selected from one or more of a diluent, a lubricant, a binder, a disintegrant, a stabilizer or a solvent.

6. The method for preparing the brucein triphenylphosphine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that: The preparation method comprises the following steps: Using brucea stearoyl alcohol (BST) as the starting material, compound BP-1-3 is prepared through step a, compound BP-4 is prepared through step b, and compound BP-5-7 is prepared through steps c and d.

7. The preparation method according to claim 6, characterized in that: The preparation method comprises the following steps: (1) Synthesis of BP-1-3 and BST-6C: Dissolve BST, acid binding agent and condensing agent in a solvent, stir at room temperature, add the corresponding carboxylic acid fragment, react at room temperature, remove the solvent, extract, wash, dry, filter and purify; (2) Synthesis of BP-4: Weigh 10-bromodecanoic acid and triphenylphosphine, dissolve in a solvent, and reflux to obtain intermediate 1. Similar to the synthesis of BP-1, dissolve BST, acid binding agent and condensing agent in a solvent, stir at room temperature, add intermediate 1, and react at room temperature; the post-treatment method is the same as step (1); (3) Synthesis of BP-5-7: Dissolve BST-6C and the corresponding triphenylphosphine in a solvent, react at room temperature, and perform post-treatment in the same manner as step (1).

8. The preparation method according to claim 7, characterized in that: The solvent is anhydrous acetonitrile, anhydrous acetone, N,N-dimethylformamide, tetrahydrofuran or dichloromethane; The acid binding agent is triethylamine, N,N-diisopropylethylamine, pyridine or 4-dimethylaminopyridine; The condensing agent is dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI).

9. Use of the brucein triphenylphosphine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 or the pharmaceutical composition according to claim 4 or claim 5 in the preparation of drugs against digestive system tumors.

10. The use according to claim 9, characterized in that: The digestive system tumor is gastric cancer, colon cancer or liver cancer.

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