Asymmetric bischalcone compound, synthesis method and application thereof

Abstract

The invention provides a novel asymmetric bischalcone compound, a synthesis method and application thereof. The invention successfully synthesizes a series of novel asymmetric bischalcone compounds and provides a specific synthesis method. These novel asymmetric bischalcone compounds show good anti-tumor activity.

Description

Technical Field

[0001] The invention relates to an asymmetric bischalcone compound, a synthesis method and application thereof. Background Art

[0002] Malignant tumors have become a prominent public health issue today. The current treatment methods mainly include surgery, radiotherapy, chemotherapy, biological therapy, etc. Among them, chemotherapy is still the main treatment method. The first-line treatment drugs are mainly classic cytotoxic drugs, which have serious toxicity and side effects. Therefore, it is crucial to identify new small molecule chemical drugs with higher efficacy and lower toxicity for the treatment of tumors.

[0003] Designing drugs using natural products as lead compounds has always been an important part of current drug discovery. Chalcones are a class of natural compounds widely distributed in vegetables, fruits, teas and various plants, with multiple pharmacological activities such as analgesia, anti-inflammatory, and anti-tumor. "Bis-chalcones" are a member of the chalcone family and also have multiple pharmacological activities. However, so far, whether isolated from natural products or chemical synthesis, bis-chalcones are compounds with symmetrical structures ( Figure 1 A) “Asymmetric bischalcone” has not been reported yet, and it is unclear whether it has pharmacological activity. The challenge of synthesis may be the reason why asymmetric bischalcone has not been reported yet. Summary of the invention

[0004] The purpose of the present invention is to overcome the shortcomings and deficiencies of the prior art and to provide an asymmetric bischalcone compound, a synthesis method and an application thereof.

[0005] The technical solution adopted by the present invention is as follows: an asymmetric bischalcone compound, the compound is as shown in the general formula (I),

[0006]

[0007] Wherein R1 and R2 are different groups.

[0008] Further, the reaction formula for synthesizing it is as follows:

[0009]

[0010] The specific steps include:

[0011] S1: triethyl orthoformate and a catalytic amount of ammonium chloride react with terephthalaldehyde to obtain compound 2;

[0012] S2: Compound 2 and R1-substituted acetophenone undergo Claisen-Schmidt reaction catalyzed by potassium hydroxide to obtain intermediates 3a-3b;

[0013] S3: Then, the protecting group of intermediate 3a-3b is removed by adding trifluoroacetic acid to obtain intermediate compound 4a-4b;

[0014] S4: Finally, the intermediate compound 4a-4b is subjected to a condensation reaction with the acetophenone substituted with R2 again under the catalysis of potassium hydroxide to obtain an asymmetric bischalcone compound.

[0015] Preferably, the feed ratio of terephthalaldehyde to triethyl orthoformate is 3:1; the feed ratio of intermediate compound 4a-4b to R2-substituted acetophenone is 1:10; the pH value of the solution in S2 is controlled to 8-9 by potassium hydroxide, and the pH value of the solution in S4 is controlled to 9-10.

[0016] Also provided is the use of the asymmetric bischalcone compound in the preparation of an anti-tumor product, specifically: R1 is 2-substituted halogen, 2-substituted alkoxy or 3-substituted alkoxy; R2 is H, a mono- or poly-substituted 2-, 3-, 4- or 5-halogen, a mono- or poly-substituted 2-, 3-, 4- or 5-alkoxy, a mono- or poly-substituted 2-, 3-, 4- or 5-halogenated alkyl, or a mono- or poly-substituted 2-, 3-, 4- or 5-alkylamino.

[0017] Preferably, the asymmetric bischalcone compound is applied to an anti-tumor product, wherein R1 is a 2-substituted halogen; most preferably, it is applied to a pharmaceutical composition for treating gastric cancer, wherein R1 is 2-Cl and R2 is 3,4,5-OCH3.

[0018] The above-mentioned asymmetric bichalcone compounds are used in anti-tumor products and pharmaceutical compositions comprising the same, which fall within the protection scope of the present invention. The pharmaceutical composition is in the form of an injection, tablet, suppository, film, capsule, ointment, aerosol, pellet, controlled release or sustained release agent and nano preparation.

[0019] The beneficial effects of the present invention are as follows: the present invention adopts a four-step method to synthesize a series of novel asymmetric bischalcone compounds, and the compounds show good anti-tumor activity.

[0020] Furthermore, a quantitative structure-activity relationship model (R 2 =0.851627), and found that the best compound J3 inhibited the formation of gastric cancer cell colonies in a concentration-dependent manner and led to cell apoptosis by inducing the expression of the pro-apoptotic protein PARP; in addition, at a daily dose of 10 mg / kg, J3 inhibited tumor growth by nearly 70% in vivo and had no obvious toxic effects on the body weight and organs of nude mice. This shows that this new compound has a good prospect for application in anti-gastric cancer drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, without paying creative labor, other drawings obtained based on these drawings still belong to the scope of the present invention.

[0022] Figure 1 The design strategy of asymmetric bis-chalcone; (A) the structural formula and synthesis of chalcone, and reported symmetric bis-chalcone; (B) the structural formula of unreported asymmetric bis-chalcone; (C) the design and screening of asymmetric bis-chalcone and active compounds based on the four-step synthesis; (D) the best compound J3;

[0023] Figure 2 The synthesis steps of compounds N1-N10 and J1-J17; reagents and conditions: a. trimethyl orthoformate, ammonium chloride, ethanol, 0°C; b. (R1 substituted) acetophenone, potassium hydroxide, ethanol, room temperature; c. trifluoroacetic acid, dichloromethane, room temperature; d. (R2 substituted) acetophenone, potassium hydroxide, ethanol, room temperature;

[0024] Figure 3 :Construction of QSAR model;(A,B,C) Molecular descriptors of compounds were calculated based on physicochemical properties and molecular structures; QSAR model was constructed by RF algorithm;

[0025] Figure 4 :J3 inhibits the colony formation of BGC-823 and SGC-7901; (A, B) The cell proliferation of BGC-823 and SGC-7901 treated with different concentrations of J3 (1 μM, 2.5 μM, 5 μM, respectively) was determined by colony formation assay;

[0026] Figure 5 :J3 induces apoptosis of BGC-823 gastric cancer cells; (A, C) BGC-823 cells were treated with different concentrations of J3 for 24 hours, and the apoptosis rate was detected by flow cytometry; (B, D) Western Blotting was used to detect the expression of pro-apoptotic protein cleaved PARP in BGC-823 cells treated with J3 for 24 hours (compared with the control group, **p<0.01, ***p<0.001);

[0027] Figure 6 :(A) Control group and experimental group, (B) tumor volume; (C) tumor mass; (D) nude mouse body weight; (E) organ coefficient;

[0028] Figure 7: The structure of the asymmetric bischalcone compound synthesized for the first time in the present invention and its antitumor activity are concisely presented. DETAILED DESCRIPTION

[0029] In order to make the objectives, technical solutions and advantages of the present invention more clear, the present invention will be further described in detail below with reference to the accompanying drawings.

[0030] Example 1. Synthesis of asymmetric bis-chalcone compounds:

[0031] The reaction formula of the asymmetric bischalcone compound is shown below:

[0032]

[0033] The preparation process is as follows:

[0034] S1: The purchased triethyl orthoformate and a catalytic amount of ammonium chloride were reacted with terephthalaldehyde at 0°C to obtain a one-side protected compound 2;

[0035] S2: Next, compound 2 and R1-substituted acetophenone were subjected to Claisen-Schmidt reaction in the presence of 10% potassium hydroxide to obtain intermediates 3a-3b;

[0036] S3: Then, the protecting group of intermediate 3a-3b is removed by adding trifluoroacetic acid to obtain intermediate compound 4a-4b;

[0037] S4: Finally, the intermediate compounds 4a-4b were again subjected to condensation reaction with acetophenone substituted with R2 under the catalysis of 10% potassium hydroxide to successfully obtain the desired compounds N1-N10 and J1-J17 (as shown in Table 1-2).

[0038] Among them, during the condition screening process for the preparation of compound 2, it was found that the feed ratio of terephthalaldehyde to triethyl orthoformate would significantly affect the yield of the target product. When the feed ratio of terephthalaldehyde to triethyl orthoformate was 3:1, the yield of the target product was optimal and could be increased to 80%. Subsequent compounds were prepared using this ratio.

[0039] Among them, during the screening of conditions for the preparation of compounds 3a-3b, it was found that the concentration of the alkali in the reaction solution would affect the yield. When the concentration of the alkali was too low, the reaction was not easy to proceed. When the concentration of the alkali was too high, additional by-products (symmetrical bischalcone compounds) would be produced. The reason for this may be that the acetal was unstable under strong alkaline conditions and decomposed into compounds 4a-4b, which then underwent aldol condensation with another molecule of substituted acetophenone, thereby forming an undesirable symmetrical bischalcone compound. Therefore, after a large number of experiments, it was finally determined that it was necessary to control the amount of catalyst added so that the pH value of the reaction solution was between 8 and 9.

[0040] Among them, during the screening of conditions for the preparation of the final products N1-N10 and J1-J17, it was found that the pH value of the reaction solution and the feed ratio of compounds 4a-4b to different substituted acetophenones would significantly affect the yield. After a large number of experiments, it was determined that the pH value of the solution was controlled at 9-10. At this time, the feed ratio of compounds 4a-4b to different substituted acetophenones was 1:10, and the yield was generally high, and the yield of some compounds could reach more than 70%.

[0041] The specific experimental process of synthesizing the best solution in this embodiment is as follows:

[0042] 1.1 Drug sources and instruments

[0043] Unless otherwise noted, all chemicals are purchased from commercial sources and used in the manner provided without further purification. Column chromatography (CC) is carried out on silica gel (200-300 mesh, Qingdao Ocean Chemical Co., Ltd., China). All compounds are verified homogeneity by silica gel thin layer chromatography (250m silica gel 60F254 glass plate). Monitor reaction process by TLC and visualize by the UV light of 254nm and 365nm. 1 H NMR and 13 CNMR spectra (400 MHz) were recorded in parts per million (ppm) using tetramethylsilane (TMS, internal standard) on a Bruker 400 Ultrashield spectrometer. Electron spray ionization mass spectrometry (ESI-MS) data were collected in positive mode using a Bruker Esquire 3000t spectrometer. 1 H and 13 The C spectrum is provided in the supplementary data. The melting point was determined using a Fisher-Johns melting point apparatus and was uncorrected. The purity of the target compound J3 was ≥95%, and it was analyzed by HPLC (HPLC) using an Agilent C18 column (4.6 mm×150 mm, 5 μm) with a gradient elution (methanol / water=85 / 15 to 100 / 0) at a flow rate of 1 mL / min.

[0044] 1.2 Preparation of Compound 2

[0045] Ammonium chloride (80.0 mg, 1.5 mmol) was added as a catalyst to a solution of terephthalaldehyde (2.0 g, 15 mmol) and triethyl orthoformate (0.74 g, 5 mmol) in ethanol (20 mL). The reaction mixture was stirred at 0 ° C overnight. The reaction process was monitored by thin layer chromatography. After the reaction was sufficient, it was quenched with water and extracted with ethyl acetate (3×20 mL) and saturated brine (3×20 mL). Next, the organic layers were combined and dried over magnesium sulfate. Oily compound 2 (0.73 g, 70%) was obtained by silica gel column chromatography with petroleum ether: ethyl acetate (10:1-15:1).

[0046] 1.3 Preparation of intermediates 3a-3b

[0047] A 10% potassium hydroxide solution (adjusted to pH 8-9) was added as a catalyst to a methanol (15 mL) solution of compound 2 (1.0 g, 4.8 mmol) and (R1 substituted) acetophenone (2.4 mmol). The reaction was carried out at room temperature and the reaction process was monitored by a thin layer chromatography spot plate. After the reaction was completed, it was quenched with water. The organic phase was extracted with ethyl acetate (3×20 mL) and washed with saturated brine (3×20 mL). Silica gel column chromatography with petroleum ether: ethyl acetate (15:1-25:1) was used to obtain oily compounds 3a-3b.

[0048] 1.4 Preparation of intermediate compounds 4a-4b

[0049] Intermediate 3a-3b (2.0mmol) was dissolved in dichloromethane (10ml), and trifluoroacetic acid (TFA) was added to adjust the pH to 2-3 for reaction. The reaction process was monitored by thin layer chromatography. After the reaction was completed, the pH was adjusted to 7 with a saturated aqueous sodium carbonate solution. The organic layer was extracted with ethyl acetate (3×20mL) and washed with saturated brine (3×20mL). Next, the organic layers were combined and dried over magnesium sulfate. The crude product was used directly in the next step without additional purification.

[0050] 1.5 Preparation method of final product (N1-N10, J1-J17)

[0051] The R2-substituted acetophenone (20 mmol) was dissolved in methanol (10 mL), and a 10% potassium hydroxide aqueous solution was added to adjust the pH value of the solution to 10. After activation at room temperature for 10 minutes, a methanol (10 mL) solution of compound 4a-4b (2.0 mmol) was added to react. The reaction process was monitored by thin layer chromatography, and after the reaction was completed, glacial acetic acid was added to adjust the pH to 7. The organic layer was extracted with ethyl acetate (3×20 mL) and washed with saturated brine (3×20 mL). Petroleum ether: dichloromethane (1:1-2:1) silica gel column chromatography or recrystallization gave the target compounds N1-N10 and J1-J17.

[0052] Through the above process, this example successfully synthesized a variety of compounds in Table 1 and Table 2, and used proton nuclear magnetic resonance ( 1 HNMR)、( 13 The structures of the asymmetric bischalcone compounds were thoroughly characterized by CNMR and electrospray ionization mass spectrometry (ESI-MS).

[0053] Table 1. Compounds N1-N10 (IC 50 Evaluation of in vitro growth inhibitory activity of

[0054]

[0055] Note: Each compound was tested in triplicate; data are expressed as mean ± standard deviation;

[0056] b - Maximum utilization of compound concentration.

[0057] Table 2. Compounds J1-J17 (IC 50 ) Evaluation of in vitro growth inhibitory activity

[0058]

[0059] Note: Each compound was tested in triplicate; data are expressed as mean ± standard deviation;

[0060] b - Maximum utilization of compound concentration.

[0061] Among them, the detection data of some compounds are as follows:

[0062] (E)-1-(2-chlorophenyl)-3-(4-((E)-3-oxo-3-(2-(trifluoromethyl)phenyl)prop-1-en-1-yl)phenyl)prop-2-en-1-one(J1).

[0063] White powder, 23% yield, mp 160.9 - 162.5 °C. 1H NMR (500 MHz, DMSO-d6): δ 7.907 (d, J = 6.4 Hz, 1H), 7.850 - 7.836 (m, 4H), 7.776 (t, J = 6.0 Hz, 1H), 7.720 (d, J = 6.0 Hz, 1H), 7.628 - 7.563 (m, 3H), 7.522 - 7.487 (m, 2H), 7.454 (s, 1H), 7.417 (s, 1H), 7.395 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 194.72 (s, 1C), 193.37 (s, 1C), 146.10 (s, 1C), 144.40 (s, 1C), 138.95 (s, 1C), 138.71 (s, 1C), 136.94 (s, 1C), 136.36 (s, 1C), 131.74 (s, 1C), 131.67 (s, 1C), 131.40 (s, 1C), 130.39 (s, 1C), 130.06 (s, 1C), 129.48 (s, 1C), 129.10 (s, 5C), 128.11 (s, 1C), 127.79 (s, 1C), 127.43 (s, 1C), 126.97 (s, 1C), 126.82 (s, 1C), 126.77 (s, 1C). EI-MS m / z: 442.1 [M+2]+, calcd for C25H16ClF3O2: 440.9.

[0064] (E)-1-(2-chlorophenyl)-3-(4-((E)-3-(2-methoxyphenyl)-3-oxoprop-1-en-1-yl)phenyl)prop-2-en-1-one (J2).

[0065] Light yellow powder, 35% yield, mp 120.3 - 122.1℃. 1H NMR (500 MHz, DMSO-d6): δ7.819 (dd, J=18.5, 7.0 Hz, 4H), 7.60 (d, J=12.6 Hz, 4H), 7.54 (s, 4H), 7.41 (t, J=16.6 Hz, 2H), 7.201 (d, J=4.0 Hz, 1H), 7.065 (t, J=7.0 Hz, 1H), 3.868 (s, 3H). 13C NMR (101 MHz, CDCl3) δ193.55 (s, 1C), 192.49 (s, 1C), 158.27 (s, 1C), 144.90 (s, 1C), 141.56 (s, 1C), 139.01 (s, 1C), 137.61 (s, 1C), 136.09 (s, 1C), 133.24 (s, 1C), 131.62 (s, 1C), 131.37 (s, 1C), 130.52 (s, 1C), 130.38 (s, 1C), 129.47 (s, 1C), 129.08 (s, 3C), 128.93 (s, 2C), 128.26 (s, 1C), 126.97 (s, 2C), 120.87 (s, 1C), 111.71 (s, 1C), 55.82 (s, 1C). EI-MS m / z: 425.2 [M+Na]+, calcd for C25H19ClO3: 402.8.

[0066] (E)-1-(2-chlorophenyl)-3-(4-((E)-3-oxo-3-(3,4,5-trimethoxyphenyl)prop-1-en-1-yl)phenyl)prop-2-en-1-one (J3).

[0067] Light yellow powder, 95% yield, mp 163.2 - 164.7 °C. 1H NMR (400 MHz, DMSO-d6): δ 8.052 (d, J = 12.4 Hz, 1H), 7.994 (d, J = 6.0 Hz, 2H), 7.885 (d, J = 6.0 Hz, 2H), 7.774 (d, J = 12.4 Hz, 1H), 7.624 - 7.566 (m, 3H), 7.515 (t, J = 4.0 Hz, 1H), 7.461 (s, 3H), 7.418 (s, 1H), 3.926 (s, 6H), 3.792 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 193.47 (s, 1C), 188.86 (s, 1C), 153.23 (s, 2C), 144.67 (s, 1C), 143.35 (s, 1C), 142.74 (s, 1C), 138.96 (s, 1C), 137.22 (s, 1C), 136.42 (s, 1C), 133.30 (s, 1C), 131.67 (s, 1C), 131.37 (s, 1C), 130.39 (s, 1C), 129.49 (s, 2C), 129.13 (s, 2C), 129.01 (s, 1C), 127.15 (s, 1C), 126.98 (s, 1C), 122.90 (s, 1C), 106.19 (s, 2C), 61.04 (s, 1C), 56.46 (s, 2C). EI-MS m / z: 463.1 [M+1]+, calcd for C27H23ClO5: 462.9.

[0068] (E)-1-(2-chlorophenyl)-3-(4-((E)-3-(3-methoxyphenyl)-3-oxoprop-1-en-1-yl)phenyl)prop-2-en-1-one (J4).

[0069] Red powder, 49% yield, mp 134.2 - 136.7℃. 1H NMR(400MHz, DMSO - d6): δ8.042 - 7.973(m, 3H), 7.876(d, J=6.4Hz, 2H), 7.808 - 7.749(m, 2H), 7.639 - 7.579(m, 4H), 7.521 - 7.505(m, 2H), 7.505 - 7.415(m, 2H), 7.257(d, J=6.4Hz, 1H), 3.863(s, 3H). 13C NMR(101MHz, CDCl3)δ193.56(s, 1C), 192.50(s, 1C), 158.27(s, 1C), 144.90(s, 1C), 141.56(s, 1C), 139.01(s, 1C), 137.62(s, 1C), 136.09(s, 1C), 133.23(s, 1C), 131.62(s, 1C), 131.38(s, 1C), 130.52(s, 1C), 130.38(s, 1C), 129.47(s, 1C), 129.08(s, 3C), 128.93(s, 2C), 128.26(s, 1C), 126.97(s, 2C), 120.87(s, 1C), 111.70(s, 1C), 55.82(s, 1C). EI - MS m / z: 403.1[M + 1]+, calcd for C25H19ClO3: 402.8.

[0070] (E)-1-(2 - bromophenyl)-3-(4 - ((E)-3-(2 - chlorophenyl)-3 - oxoprop - 1 - en - 1 - yl)phenyl)prop - 2 - en - 1 - one (J5).

[0071] White powder, 45% yield, mp 151.2 - 153.3 °C. 1H NMR (400 MHz, DMSO-d6): δ 8.159 (d, J = 8.4 Hz, 2H), 8.070 (d, J = 15.6 Hz, 1H), 7.960 (dd, J = 8.4, 30.4 Hz, 4H), 7.838 - 7.788 (m, 3H), 7.66–7.58 (m, 3H), 7.54 (d, J = 1.7 Hz, 1H), 7.461 (d, J = 8.4 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 193.49 (s, 1C), 190.22 (s, 1C), 144.71 (s, 1C), 143.43 (s, 1C), 139.01 (s, 1C), 138.05 (s, 1C), 137.23 (s, 1C), 136.45 (s, 1C), 133.01 (s, 1C), 131.63 (s, 1C), 130.39 (s, 1C), 129.48 (s, 1C), 129.13 (s, 2C), 128.99 (s, 3C), 128.73 (s, 2C), 128.55 (s, 2C), 127.18 (s, 1C), 126.96 (s, 1C), 123.28 (s, 1C). EI-MS m / z: 493.1 [M+K]+, calcd for C24H16BrClO2: 451.7.

[0072] (E)-1-(2-chlorophenyl)-3-(4-((E)-3-(3,4-dichlorophenyl)-3-oxoprop-1-en-1-yl)phenyl)prop-2-en-1-one (J6).

[0073] White powder, 48% yield, mp 148.3 - 149.8 °C. 1H NMR (400 MHz, DMSO-d6): δ 8.453 (s, 1H), 8.142 (d, J = 6.4 Hz, 1H), 8.078 (d, J = 12.4 Hz, 1H), 8.005 (d, J = 6.4 Hz, 2H), 7.897 - 7.874 (m, 2H), 7.823 (t, J = 13.6 Hz, 2H), 7.619 - 7.563 (m, 3H), 7.524 - 7.479 (m, 1H), 7.446 - 7.390 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 193.47 (s, 1C), 187.71 (s, 1C), 144.59 (s, 2C), 138.86 (s, 1C), 137.56 (s, 1C), 137.48 (s, 1C), 136.77 (s, 1C), 136.71 (s, 1C), 131.66 (s, 1C), 130.83 (s, 1C), 130.45 (s, 1C), 130.35 (s, 1C), 129.39 (s, 1C), 129.15 (s, 3C), 129.13 (s, 3C), 127.55 (s, 1C), 127.34 (s, 1C), 126.96 (s, 1C), 122.05 (s, 1C). EI-MS m / z: 442.9 [M+1]+, calcd for C24H15Cl3O2: 441.7.

[0074] (E)-1-(2-chlorophenyl)-3-(4-((E)-3-(3,4-dimethoxyphenyl)-3-oxoprop-1-en-1-yl)phenyl)prop-2-en-1-one (J7).

[0075] Yellow powder, 75% yield, mp 147.1 - 148.0 °C. 1H NMR (500 MHz, DMSO-d6) δ 8.05 (d, J = 15.6 Hz, 1H), 7.95 (dd, J = 11.1, 5.0 Hz, 3H), 7.86 (d, J = 8.3 Hz, 2H), 7.73 (d, J = 15.5 Hz, 1H), 7.64–7.55 (m, 4H), 7.53–7.47 (m, 1H), 7.42 (d, J = 20.9 Hz, 2H), 7.11 (d, J = 8.5 Hz, 1H), 3.86 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 193.49 (s, 1C), 188.25 (s, 1C), 153.53 (s, 1C), 149.41 (s, 1C), 144.77 (s, 1C), 142.59 (s, 1C), 139.04 (s, 1C), 137.47 (s, 1C), 136.26 (s, 1C), 131.61 (s, 1C), 131.40 (s, 1C), 131.20 (s, 1C), 130.38 (s, 1C), 129.47 (s, 1C), 129.10 (s, 2C), 128.90 (s, 2C), 127.09 (s, 1C), 126.95 (s, 1C), 123.14 (s, 1C), 122.93 (s, 1C), 110.86 (s, 1C), 110.06 (s, 1C), 56.16 (s, 1C), 56.12 (s, 1C). EI-MS m / z: 434.1 [M+1]+, calcd for C26H21ClO4: 432.9.

[0076] (E)-1-(4-bromophenyl)-3-(4-((E)-3-(2-chlorophenyl)-3-oxoprop-1-en-1-yl)phenyl)prop-2-en-1-one (J8).

[0077] White powder, 67% yield, mp 155.2 - 156.6 °C. 1H NMR (400 MHz, DMSO-d6): δ 8.130 (d, J = 6.4 Hz, 1H), 7.979 (d, J = 6.4 Hz, 1H), 7.890 (d, J = 6.4 Hz, 7H), 7.741 (d, J = 6.4 Hz, 6H), 7.624 - 7.582 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 194.36 (s, 1C), 193.47 (s, 1C), 144.92 (s, 1C), 144.56 (s, 1C), 140.97 (s, 1C), 138.93 (s, 1C), 136.76 (s, 1C), 136.70 (s, 1C), 133.53 (s, 1C), 131.69 (s, 1C), 131.64 (s, 1C), 131.38 (s, 1C), 130.39 (s, 1C), 129.49 (s, 1C), 129.30 (s, 1C), 129.13 (s, 4C), 127.49 (s, 1C), 127.33 (s, 1C), 127.16 (s, 1C), 126.98 (s, 1C), 119.56 (s, 1C). EI-MS m / z: 452.3 [M+1]+, calcd for C24H16BrClO2: 451.7.

[0078] (E)-1-(2-chlorophenyl)-3-(4-((E)-3-(3,4-dimethoxyphenyl)-3-oxoprop-1-en-1-yl)phenyl)prop-2-en-1-one (J9).

[0079] Red powder, 67% yield, mp 174.5 - 177.3℃. 1H NMR(500MHz, DMSO-d6): δ7.98(s, 1H), 7.84(dd, J=21.3, 8.2Hz, 4H), 7.66–7.59(m, 5H), 7.53(dd, J=15.2, 8.3Hz, 2H), 7.46(s, 1H), 6.72(s, 1H), 6.67(d, J=10.2Hz, 1H), 3.93(s, 3H), 3.88(s, 3H). 13C NMR(101MHz, CDCl3) δ193.60(s, 1C), 190.00(s, 1C), 164.47(s, 1C), 160.58(s, 1C), 145.05(s, 1C), 140.45(s, 1C), 139.04(s, 1C), 138.02(s, 1C), 135.81(s, 1C), 133.08(s, 1C), 131.59(s, 1C), 131.37(s, 1C), 130.37(s, 1C), 129.46(s, 1C), 129.07(s, 2C), 128.82(s, 2C), 128.50(s, 1C), 126.95(s, 1C), 126.82(s, 1C), 122.01(s, 1C), 105.39(s, 1C), 98.66(s, 1C), 55.82(s, 1C), 55.62(s, 1C). EI-MS m / z: 433.1[M + 1]+, calcd for C26H21ClO4: 432.9.

[0080] (2E,2'E)-3,3'-(1,4-phenylene)bis(1-(2-chlorophenyl)prop-2-en-1-one)(J10).

[0081] White powder, 89% yield, mp 151.3 - 152.6℃. 1H NMR(400MHz, DMSO-d6): δ7.847(s, 4H), 7.616 - 7.557(m, 6H), 7.494(q, J=6.4Hz, 3H), 7.441(s, 1H), 7.404(s, 1H), 7.372(s, 1H). 13C NMR(101MHz, CDCl3) δ193.44(s, 2C), 144.57(s, 2C), 138.94(s, 2C), 136.73(s, 2C), 131.68(s, 2C), 131.38(s, 2C), 130.39(s, 2C), 129.49(s, 2C), 129.13(s, 4C), 127.31(s, 2C), 126.98(s, 2C). EI-MS m / z: 409.0[M+2]+, calcd for C24H16Cl2O2: 407.3.

[0082] (E)-1-(2-chlorophenyl)-3-(4-((E)-3-(2,5-dimethoxyphenyl)-3-oxoprop-1-en-1-yl)phenyl)prop-2-en-1-one (J11).

[0083] White powder, 56% yield, mp 129.3 - 131.3℃. 1H NMR(400MHz, DMSO-d6): δ7.845(dd, J=8.4, 7.2Hz, 4H), 7.622(t, J=7.6Hz, 3H), 7.599 - 7.547(m, 4H), 7.439(d, J=20.4Hz, 1H), 7.168(s, 2H), 7.089(s, 1H), 3.851(s, 3H), 3.780(s, 3H). 13C NMR(101MHz, CDCl3)δ192.45(s, 1C), 192.06(s, 1C), 153.73(s, 1C), 152.74(s, 1C), 143.28(s, 1C), 141.92(s, 1C), 137.00(s, 1C), 132.88(s, 1C), 129.54(s, 1C), 128.89(s, 4C), 128.53(s, 1C), 128.19(s, 1C), 127.77(s, 1C), 126.28(s, 1C), 120.86(s, 1C), 119.49(s, 1C), 118.95(s, 1C), 114.50(s, 1C), 113.83(s, 1C), 113.48(s, 1C), 112.61(s, 1C), 56.56(s, 1C), 55.90(s, 1C). EI-MS m / z: 433.1[M+1]+, calcd for C26H21ClO4: 432.9.

[0084] (E)-1-(2-chlorophenyl)-3-(4-((E)-3-oxo-3-(3-(trifluoromethyl)phenyl)prop-1-en-1-yl)phenyl)prop-2-en-1-one (J12).

[0085] Colorless liquid (colorless liquid), 25% yield. 1H NMR (500 MHz, DMSO-d6) δ 8.52–8.45 (m, 2H), 8.14 (d, J=15.6 Hz, 1H), 8.06 (d, J=7.6 Hz, 1H), 8.02 (d, J=8.2 Hz, 2H), 7.90 (d, J=8.2 Hz, 2H), 7.86–7.81 (m, 2H), 7.65–7.56 (m, 3H), 7.52 (t, J=7.6 Hz, 1H), 7.44 (d, J=12.2 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 193.41 (s, 1C), 189.36 (s, 1C), 144.68 (s, 1C), 144.45 (s, 1C), 140.88 (s, 1C), 138.97 (s, 1C), 136.87 (s, 1C), 136.75 (s, 1C), 131.67 (s, 1C), 130.39 (s, 1C), 129.49 (s, 1C), 129.16 (s, 3C), 129.13 (s, 3C), 128.81 (s, 3C), 127.40 (s, 1C), 126.97 (s, 1C), 125.79 (s, 1C), 125.75 (s, 1C), 122.68 (s, 1C). EI-MS m / z: 442.9 [M+2]+, calcd for C25H16ClF3O2: 440.8.

[0086] (E)-1-(2-chlorophenyl)-3-(4-((E)-3-(2,5-dichlorophenyl)-3-oxoprop-1-en-1-yl)phenyl)prop-2-en-1-one (J13).

[0087] White powder, 44% yield, mp 178.4 - 180.9 °C. 1H NMR (500 MHz, DMSO-d6): δ 7.89–7.84 (m, 3H), 7.73 (s, 1H), 7.64 (s, 2H), 7.62–7.56 (m, 3H), 7.51 (dd, J=24.2, 18.9 Hz, 3H), 7.41 (dt, J=16.1, 5.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 190.24 (s, 1C), 188.86 (s, 1C), 144.41 (s, 1C), 143.48 (s, 1C), 139.65 (s, 1C), 138.04 (s, 1C), 137.19 (s, 1C), 136.59 (s, 1C), 135.05 (s, 1C), 133.04 (s, 1C), 132.91 (s, 1C), 130.07 (s, 1C), 129.14 (s, 2C), 129.04 (s, 2C), 128.75 (s, 2C), 128.63 (s, 1C), 128.57 (s, 2C), 126.61 (s, 1C), 123.22 (s, 1C), 122.38 (s, 1C). EI-MS m / z: 443.1 [M+2]+, calcd for C24H15Cl3O2: 441.7.

[0088] (E)-1-(2-chlorophenyl)-3-(4-((E)-3-(4-methoxyphenyl)-3-oxoprop-1-en-1-yl)phenyl)prop-2-en-1-one (J14).

[0089] Yellow powder, 62% yield, mp 126.3 - 128.0 °C. 1H NMR (400 MHz, DMSO-d6): δ 8.218 (d, J = 9.2 Hz, 2H), 8.076 (d, J = 15.6 Hz, 1H), 7.935 (dd, J = 36.8, 8.4 Hz, 4H), 7.741 (d, J = 15.6 Hz, 1H), 7.637 - 7.571 (m, 3H), 7.543 - 7.497 (m, 1H), 7.444 (d, J = 10.8 Hz, 2H), 7.112 (d, J = 8.8 Hz, 2H), 3.89 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 193.56 (s, 1C), 188.34 (s, 1C), 163.62 (s, 1C), 144.86 (s, 1C), 142.57 (s, 1C), 139.00 (s, 1C), 137.46 (s, 1C), 136.20 (s, 1C), 131.62 (s, 1C), 131.38 (s, 1C), 130.90 (s, 3C), 130.38 (s, 1C), 129.47 (s, 1C), 129.11 (s, 2C), 128.91 (s, 2C), 127.05 (s, 1C), 126.96 (s, 1C), 123.08 (s, 1C), 113.96 (s, 2C), 55.56 (s, 1C). EI-MS m / z: 425.2 [M+Na]+, calcd for C25H19ClO3: 402.9.

[0090] (E)-1-(2-chlorophenyl)-3-(4-((E)-3-(4-(dimethylamino)phenyl)-3-oxoprop-1-en-1-yl)phenyl)prop-2-en-1-one (J15).

[0091] Yellow powder, 34% yield, mp 137.0 - 139.5 °C. 1H NMR (400 MHz, DMSO-d6): δ 8.092 (d, J = 8.8 Hz, 2H), 8.039 (d, J = 15.6, 1 Hz), 7.910 (dd, J = 31.2, 8.0 Hz, 4H), 7.72–7.55 (m, 4H), 7.55–7.38 (m, 3H), 6.784 (d, J = 8.8 Hz, 2H), 3.070 (m, 6H). 13C NMR (101 MHz, CDCl3) δ 193.60 (s, 1C), 187.34 (s, 1C), 153.57 (s, 1C), 145.07 (s, 1C), 141.14 (s, 1C), 139.08 (s, 1C), 138.02 (s, 1C), 135.80 (s, 1C), 131.55 (s, 1C), 131.39 (s, 1C), 130.93 (s, 2C), 130.37 (s, 1C), 129.45 (s, 1C), 129.07 (s, 2C), 128.75 (s, 2C), 126.93 (s, 1C), 126.86 (s, 1C), 125.86 (s, 1C), 123.58 (s, 1C), 110.90 (s, 2C), 40.07 (s, 2C). EI-MS m / z: 416.9 [M+1]+, calcd for C26H22ClNO2: 415.9.

[0092] (E)-1-(2-chlorophenyl)-3-(4-((E)-3-(4-ethoxyphenyl)-3-oxoprop-1-en-1-yl)phenyl)prop-2-en-1-one (J16).

[0093] Light yellow powder, 71% yield, mp 125.4 - 126.7℃. 1H NMR(500MHz, DMSO-d6): δ8.175(d, J=6.0Hz, 2H), 8.308(dd, J=15.5, 2.5Hz, 1H), 7.949(d, J=6.0Hz, 2H), 7.858(d, J=6Hz, 2H), 7.711(d, J=15.5Hz, 1H), 7.609 - 7.554(m, 3H), 7.514 - 7.364(m, 3H), 7.064(d, J=6.0Hz, 2H), 4.139(q, J=7.0Hz, 2H), 1.354(t, J=7.0Hz, 3H). 13C NMR(101MHz, CDCl3)δ193.56(s, 1C), 188.34(s, 1C), 163.07(s, 1C), 144.87(s, 1C), 142.58(s, 1C), 142.49(s, 1C), 139.01(s, 1C), 137.50(s, 1C), 136.18(s, 1C), 131.62(s, 1C), 130.91(s, 2C), 130.39(s, 1C), 129.47(s, 1C), 129.12(s, 2C), 128.91(s, 2C), 127.04(s, 1C), 126.96(s, 1C), 123.12(s, 1C), 123.10(s, 1C), 114.39(s, 1C), 113.96(s, 1C), 63.86(s, 1C), 14.73(s, 1C). EI-MS m / z: 419.2[M+1]+, calcd for C26H21ClO3: 417.9.

[0094] (E)-1-(2-chlorophenyl)-3-(4-((E)-3-(4-nitrophenyl)-3-oxoprop-1-en-1-yl)phenyl)prop-2-en-1-one (J17).

[0095] Yellow powder, 22% yield, mp 177.8-179.0℃.1H NMR (400MHz, DMSO-d6): δ8.409 (s, 4H), 7.965 (qd, J=34.0, 16.0Hz, 6H), 7.618 (t, J=8.0Hz, 3H), 7.543-7.504 (m, 1H), 7.454 (d, J=6.4Hz, 2H).13C NMR(101MHz, CDCl3)δ193.42(s,1C),188.74(s,1C),150.21(s,1C),145.40(s,1C), 144.34(s,1C),142.82(s,1C),138.93(s,1C),137.12(s,1C),136.49(s,1C),131.74 (s,1C),131.41(s,1C),130.42(s,1C),129.52(s,1C),129.48(s,2C),129.26(s,2C) ,129.22(s,2C),127.52(s,1C),127.01(s,1C),123.97(s,2C),122.32(s,1C).EI-MS m / z:418.1[M+1]+,calcd for C24H16ClNO4:417.8.

[0096] To date, asymmetric compounds with different benzene ring substituents on both sides of the dialdehyde have not been reported. In Example 1 of the present invention, we conducted further exploration based on the known single-side aldehyde protection method, used triethyl orthoformate to protect the symmetrical dialdehyde, and successfully synthesized an asymmetric bischalcone compound through a four-step reaction. This strategy provides a reference for the synthesis of such compounds.

[0097] Example 2. Evaluation of compound growth inhibitory activity in vitro:

[0098] GC cell lines BGC-823, SGC-7901 and AGS were selected, and the in vitro antitumor activity of the synthesized compounds was evaluated by the MTT method. Human gastric cancer cells SGC-7901, BGC-823 and AGS were purchased from the Chinese Type Culture Collection (Wuhan University). All cells were cultured in RPMI-1640 medium (Gibco, USA) containing 100U / mL penicillin, 100U / mL streptomycin and 10% fetal bovine serum (Gibco, USA), and cultured at 37°C and 5% carbon dioxide atmosphere. Cells in the logarithmic growth phase were taken for the next experiment.

[0099] SGC-7901, BGC-823 and AGS cells were cultured at 3×10 3Cells / well were seeded in a 96-well plate at a density of 1.5 μg / mL and cultured for 24 h. Tumor cells were incubated with the synthesized compounds for 72 h. After treatment, MTT solution at a concentration of 5 mg / mL (Solanum chinensis) was added to each well and cultured in an incubator for another 4 h. Then, 150 μL DMSO was added to each well using an MTT solution pipette, shaken for 10 min, and the absorbance of each well was measured at a wavelength of 490 nm using a microplate reader (SpectraMax M2 / M2e, Molecular Devices, Samsung, California, USA) (A). The growth inhibition rate was calculated by comparing it with the control group. Inhibition rate (%) = [(1-A experimental group / A control group) × 100%]. The half-inhibitory concentration value of each compound was calculated by GraphPad 8.0 (San Diego, CA).

[0100] As shown in Table 1, among all the synthesized compounds, not all asymmetric bichalcone compounds have antitumor activity. Among them, only compounds N2, N3, N4, N8, and N9 have good antitumor activity. It can be further found that compounds containing halogen substitution at position 2 on the benzene ring (N2, N3, N4) exhibit better antitumor activity.

[0101] We further selected compounds containing chlorine atom substituents at the 2nd position for antitumor activity experiments. As shown in Table 2, all compounds containing chlorine atoms showed good antitumor activity against the three tumor cell lines. It can be found that compound J3 with a stronger electron-donating group has better activity than N3. The half-inhibitory concentration values ​​of J3 in BGC-823, SGC-7901 and AGS cells were 0.9±0.1, 0.9±0.0 and 0.7±0.1 μM, respectively. Interestingly, when the nitro group was attached to the "B ring" (J17), its biological activity was significantly reduced. In addition, there were differences in activity within different electron donor groups and within different acceptor groups. In summary, we selected compound J3 as the best compound and further studied its biological activity.

[0102] Example 3. Quantitative evaluation of structure-activity relationship

[0103] Quantitative structure-activity relationship (QSAR) studies are widely used in drug development and are one of the main tools to guide drug design. In recent years, QSAR modeling based on machine learning has been widely used, and random forest (RF) is one of the better algorithms for building QSAR models. RF is an algorithm that integrates multiple decision trees based on the idea of ​​ensemble learning. By sampling the total data set, multiple different sub-data sets are generated, a decision tree is trained for each sub-data set, and then all decision trees are integrated into a forest to predict the final result. In order to further prove the structure-activity relationship of these compounds in inhibitory activity, we used the RF algorithm to construct a regression QSAR model. Figure 3As shown, an excellent QSAR model was obtained using high squared regression coefficients and appropriate RF (BGC-823 cell R 2 =0.851627, SCG-7901 cell R 2 =0.830995, AGC cell R 2 =0.843420), and this model is used as a certain instruction function for subsequent research.

[0104] Example 4. Anti-gastric cancer activity test of J3

[0105] 4.1J3 inhibits the formation of GC cell colonies

[0106] We used BGC-823 and SGC-7901 cells to further determine its inhibitory effect on colony formation. The specific operation method was as follows: SGC-7901 and BGC-823 cells were seeded in 6-well plates (3×10 3 Cells) were incubated with a certain concentration of J3 and DMSO in a 37°C and 5% CO2 incubator. The cells were cultured for 14 days and then fixed with 4% paraformaldehyde for 15 min and then stained with 1% crystal violet for 15 min at room temperature.

[0107] The results showed that J3 inhibited the colony formation in both GC cell lines in a concentration-dependent manner, and exhibited highly significant activity at a concentration of 2.5 μM ( Figure 4 ). In summary, J3 has a good inhibitory effect on the growth of GC cells.

[0108] 4.2J3 induces GC cell apoptosis

[0109] Apoptosis is a programmed death process controlled by genes. Studies have shown that apoptosis is associated with the occurrence and development of tumors. Disorders in apoptosis are a hallmark of cancer, and disruption of apoptosis can allow cancer cells to grow indefinitely. Therefore, promoting apoptosis can achieve anti-tumor effects.

[0110] The specific operation is as follows: BGC-823 cells are cultured at 3x 10 5 The cells were seeded in 6-well plates at a density of 10 cells / mL and treated with different concentrations of J3 for 24 h. After treatment, apoptosis was detected using an apoptosis detection kit (BD, USA) with double staining of FITC-annexinV (early apoptosis) and PI (late apoptosis). Finally, the cells were collected and the samples were analyzed by flow cytometry (FACS Calibur, BD, USA). FlowJo software was used for quantitative analysis of apoptosis. Cell apoptosis rate = late apoptosis rate + early apoptosis rate.

[0111] Western blotting: Cells were lysed with RIPA buffer (BOSTER, China) containing 1% phosphatase inhibitor (P1260, Solarbio, Beijing). The protein concentration of all samples was determined using the Bradford protein assay kit (Bio-Rad, Harkles, CA). The lysates were separated by SDS-PAGE electrophoresis and then transferred to PVDF membranes (Milwell, Billerica, MA, USA). The cell membranes were blocked with 5% skim milk for 1.5 h at room temperature, eluted with TBST, and incubated with primary antibodies overnight at 4 °C. After washing three times with TBST, the membranes were incubated with peroxidase (HRP)-conjugated secondary antibodies for 1.5 h at room temperature, eluted three times with TBST, and exposed in an exposure device. The ECL kit (Bio-Rad, Harkles, CA) was used for detection, and the bands were analyzed using Image laboratory software (NIH, Bethesda, MD, USA). The following primary antibodies were used: rabbit anti-GAPDH (1:10000, 20536-1-AP, Proteintech, China), rabbit anti-cleaved-PARP (1:1000, 5625S, Cell Signaling Technology, USA). The following secondary antibodies were used: HRP-conjugated Affinity Pure goat anti-rabbit IgG (H+L) antibody (1:5000, SA00001-2, Proteintech, China).

[0112] In this study, flow cytometry and Western blotting were used to analyze the effects of compounds on GC cell apoptosis and the expression of pro-apoptotic proteins. Figure 4 As shown in Figure 2, J3 induced apoptosis in BGC-823 cells in a concentration-dependent manner. When the concentration of J3 was 5 μM, the apoptosis rate of BGC-823 cells exceeded 50% ( Figure 5 A, C). Thus, J3 has a good apoptosis-promoting effect on GC cells. Then the effect of the compound on the expression of apoptosis-related protein PARP was evaluated. J3 concentration-dependently enhanced the expression of PARP in BGC-823 cells ( Figure 5 B, D). In summary, J3 significantly promoted GC cell apoptosis.

[0113] 4.3 Antitumor activity of J3 in vivo

[0114] A BGC-823 nude mouse subcutaneous transplant tumor model was established to study the antitumor activity of J3 in vivo.

[0115] Curcumin is a natural product with a similar structural skeleton to bichalcone and has a wide range of anti-tumor activity, so it was selected as a positive control. Curcumin (10 mg / kg) and J3 (10 mg / kg) were administered once a day for 14 consecutive days, and the changes in tumor volume and body weight of nude mice were tracked every day.

[0116] For the BGC-823 xenograft tumor model, mice were placed under specific pathogen-free (SPF) conditions at 18-23°C and 50-60% humidity. BGC-823 cells in the logarithmic growth phase were resuspended in serum-free 1640 medium and adjusted to a density of 1.5×10^7 cells / mL. Then 0.2 mL of the cell suspension was injected into the right axilla of each nude mouse.

[0117] The specific operation is: when the average tumor size reaches 50mm 3 At 14:30 pm, nude mice were randomly divided into 3 groups and treated with J3 (10 mg / kg ip) or curcumin (10 mg / kg ip) once a day. Tumor size was measured every day and calculated according to the formula: tumor size = length × width 2 / 2. After 14 days of treatment, mice were euthanized by cervical dislocation. Tumors and important organs were removed, snap-frozen in liquid nitrogen or fixed in 4% paraformaldehyde, embedded in paraffin, sectioned, and stained with HE. All experimental procedures were approved by the Ethics Committee of Wenzhou Medical University.

[0118] The results showed that J3 could significantly inhibit tumor growth compared with the vehicle (P<0.01), and its tumor inhibition effect was better than that of curcumin (P<0.01, Figure 6 AC). Importantly, at therapeutic doses, J3 had no effect on the body weight of nude mice ( Figure 6 D), organ coefficient (organ weight / body weight × 100%) showed that J3 had no obvious toxicity to the major organs of nude mice ( Figure 6 E). In summary, J3 has a good ability to inhibit tumor growth and good safety in vivo.

[0119] All the results of the above experiments are expressed as mean ± standard deviation (SD). All experiments were repeated at least 3 times. We used t-test in GraphPad 8.0 (GraphPad, San Diego, CA, USA) to compare statistical data. The difference was considered statistically significant when the P value was less than 0.05 (p < 0.05).

[0120] The above experiments show that most of the asymmetric bichalcone compounds provided by the present invention can strongly inhibit the growth of GC cells. The QSAR model of the anti-tumor activity of the compound on three tumor cell lines was established by the RF method. The model has good fitting and performance, and the regression coefficients are all over 0.8. The half-inhibitory concentration values ​​of the best compound J3 in BGC-823, SGC-7901 and AGS cells are 0.9±0.1, 0.9±0.0 and 0.7±0.1 μM, respectively. The experiment confirmed that compound J3 inhibited the colony formation of GC cells in a concentration-dependent manner, induced the expression of apoptotic protein cleavage PARP, and promoted the apoptosis of GC cells. The subcutaneous tumor metastasis experiment in nude mice showed that a dose of 10 mg / kg of compound J3 could inhibit tumor growth by about 70%, significantly inhibiting the tumorigenesis of GC cells. In addition, no obvious toxicity and side effects were observed within the dosage range.

[0121] In summary, the present invention designed and synthesized asymmetric bichalcone compounds, some of which have good in vitro anti-gastric cancer activity, such as N2, N3, N4, N8, N9, J1-J16. Among them, the best active compound J3 has very significant in vitro and in vivo anti-gastric cancer activity, and is expected to be further studied as a new candidate drug with anti-tumor activity.

[0122] The above disclosure is only the preferred embodiment of the present invention, which certainly cannot be used to limit the scope of the present invention. Therefore, equivalent changes made according to the claims of the present invention are still within the scope of the present invention.

Claims

1. An asymmetric bischalcone compound, characterized in that: The compound is as shown in general formula (I), Wherein R1 is 2-Cl and R2 is 3,4,5-OCH3.

2. The method for synthesizing an asymmetric bischalcone compound according to claim 1, characterized in that The reaction formula is as follows: The following steps are involved: S1: triethyl orthoformate and a catalytic amount of ammonium chloride react with terephthalaldehyde to obtain compound 2; S2: Compound 2 and R1-substituted acetophenone undergo Claisen-Schmidt reaction catalyzed by potassium hydroxide to obtain intermediates 3a-3b; S3: Then, the protecting group of intermediate 3a-3b is removed by adding trifluoroacetic acid to obtain intermediate compound 4a-4b; S4: Finally, the intermediate compound 4a-4b is subjected to a condensation reaction with the acetophenone substituted with R2 again under the catalysis of potassium hydroxide to obtain an asymmetric bischalcone compound.

3. The method for synthesizing an asymmetric bischalcone compound according to claim 2, characterized in that: In step S1, the feed ratio of terephthalaldehyde to triethyl orthoformate is 3:1; in step S4, the feed ratio of the intermediate compound 4a-4b to the R2-substituted acetophenone is 1:

10.

4. The method for synthesizing an asymmetric bischalcone compound according to claim 2, characterized in that: The pH value of the reaction solution in step S2 is controlled to be 8-9 by potassium hydroxide, and the pH value of the reaction solution in step S4 is controlled to be 9-10.

5. A product for anti-tumor use, comprising the asymmetric bischalcone compound according to claim 1.

6. The anti-tumor product according to claim 5, characterized in that: The anti-tumor product is a pharmaceutical composition for treating gastric cancer.

7. The anti-tumor product according to claim 5, characterized in that: The anti-tumor product is a pharmaceutical composition for treating gastric cancer, and the pharmaceutical composition is in the form of an injection, tablet, suppository, film, capsule, ointment, aerosol, pellet, controlled-release or sustained-release agent, and nano-preparation.

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