CN111269104B - Chalcone analogue and application thereof - Google Patents

Chalcone analogue and application thereof Download PDF

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CN111269104B
CN111269104B CN202010084658.0A CN202010084658A CN111269104B CN 111269104 B CN111269104 B CN 111269104B CN 202010084658 A CN202010084658 A CN 202010084658A CN 111269104 B CN111269104 B CN 111269104B
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郑小辉
刘志国
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Wenzhou Medical University
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Abstract

The invention discloses a chalcone analogue and application thereof, wherein the structure of the chalcone analogue is shown as a formula (I), and R is selected from substituted or unsubstituted aryl or heteroaryl; the substituents on the aryl or heteroaryl groups are selected from C 1 ～C 5 Alkyl, C 1 ～C 5 Alkoxy, halogen or trifluoromethyl. The test result of in vitro anti-tumor activity shows that most of chalcone analogues have higher anti-tumor activity.

Description

Chalcone analogue and application thereof
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a chalcone analogue and application thereof.
Background
Telomeres are special structures of linear chromosome ends of eukaryotic cells, and have the functions of protecting chromosome ends and maintaining genome stability. Telomeres at the ends of linear chromosomes can avoid recognition of the ends of linear chromosomes as DNA damage and inhibit DNA damage response mechanisms. In human cells, telomeres consist of the telomere DNA repeat 5'-TTAGGG-3' with the telomere binding protein "Shellerin". The protein complex Shellerin consists of six proteins: POT1 (protection of telomeres 1), TRF1 (telomeric repeat binding factor 1), TRF2 (telomeric repeat binding factor 2), TIN2 (TRF 1-interacting protein 2), TPP1 (the POT1-and TIN2-organizing protein), RAP1 (repeater/activator protein) ]. In tissue cells, abnormal expression of a protein in the Shelterin complex or dysfunction thereof can disrupt the integrity of the telomere and its genomic stability.
TRF2 is a homolog of TRF1 found in Broccoli et al 1997, and can bind directly to telomere double-stranded DNA, and is a specific telomere sequence binding protein. TRF2 has a molecular weight of 66KD, is composed of 500 amino acids, and is genetically localized at 16q22.1.TRF2 also contains 3 important domains: an amino-terminal basic region, a centrally located dimer conservation sequence, and a carboxy-terminal Myb-type DNA domain. The deletion of TRF2 affects T-loop formation, resulting in chromosome end fusion. Furthermore, the presence of TRF2 on telomeres inhibits the occurrence of the DNA damage repair mechanism NHEJ. Numerous studies have shown that TRF2 is highly expressed in tumor tissue. Thus, TRF2 can be a potential target for the treatment of malignant tumors.
Kava B (Flavokawain B) is a natural chalcone compound in kava root, which is a medicinal plant, and has wide biological activity, such as anti-tumor, antioxidant, and prevention and treatment of diabetes and its complications. At present, research on kava piperine at home and abroad is mostly focused on anxiolytic and antidepressant effects from literature reports, but research on anti-tumor activity of kava piperine is not much reported. Compounds due to the chalcone structure have various anticancer activities such as inhibiting tumor proliferation, deterioration and migration. On the basis, the invention provides novel chalcone derivatives of kava-kava B, which are particularly suitable for diseases caused by high expression or mutation of TRF2, especially tumors and cancers.
Disclosure of Invention
The invention provides a chalcone analogue and application thereof, and the chalcone analogue has better anti-tumor activity.
A chalcone analogue has a structure shown in a formula (I):
in formula (I), R is selected from various substituted or unsubstituted aryl or heteroaryl groups; the substituents on the aryl or heteroaryl groups are selected from C 1 ～C 5 Alkyl, C 1 ～C 5 Alkoxy, halogen or trifluoromethyl.
The invention designs a novel chalcone compound by a drug design method based on a kava piperine B structure skeleton. The test result of in vitro anti-tumor activity shows that most of chalcone analogues have higher anti-tumor activity.
Preferably, the aryl is phenyl; the heteroaryl is thienyl, pyrimidinyl or 2, 3-dihydrobenzo [ b ] [1,4] dioxinyl.
Preferably, the substituents on the aryl or heteroaryl groups are selected from methyl, ethyl, N-dimethylamino, halogen, methoxy.
Preferably, said R is selected from the group consisting of:
the invention also provides application of the chalcone analogues, and the chalcone analogues are used for preparing antitumor drugs.
Preferably, the chalcone analogues treat tumors and tumor-related disorders by inhibiting the expression of TRF 2.
Preferably, the tumor-associated diseases include, but are not limited to: cancers, such as liver cancer (including small cell liver cancer), bladder cancer, breast cancer, colon cancer, kidney cancer, lung cancer, esophagus cancer, gall bladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, and skin cancer (including squamous cell carcinoma); hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, hodgkin's lymphoma, non-hodgkin's lymphoma, mantle cell lymphoma, hairy cell lymphoma, and Burkett's lymphoma; hematopoietic tumors of the myeloid lineage, including acute and chronic myelogenous leukemia, myelodysplastic syndrome, and promyelocytic leukemia; multiple myeloma; tumors of mesenchymal origin, including fibroids and rhabdomyosarcoma; other tumors, including melanoma, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, keratoxanthoma, thyroid cyst carcinoma and kaposi's sarcoma.
Most preferably, the chalcone analogues have the following structural formula:
the activity test shows that the compound has the best anti-tumor activity.
The invention also provides a pharmaceutical preparation which comprises an effective component and a pharmaceutical adjuvant, wherein the effective component comprises the chalcone analogues.
Preferably, the pharmaceutical preparation is any one of injection, tablet, capsule, aerosol, suppository, film, dripping pill, ointment, controlled release agent, sustained release agent or nanometer preparation.
Compared with the prior art, the invention has the beneficial effects that: based on the structural framework of kava piperine B, a novel chalcone compound is designed and synthesized through a drug design method. The compound has excellent effect of inhibiting TRF2 over-expression or abnormal activated cell proliferation and excellent effect of inhibiting TRF2 kinase in specificity or broad spectrum, and has good effect of inhibiting drug-resistant mutant strain, so that tumor can be treated efficiently.
The present invention will be described in detail below with reference to specific drawings and examples for the purpose of facilitating understanding. It is to be expressly noted that the specific examples and the drawings are for illustrative purposes only and are not to be construed as limiting the scope of the present invention. It will be apparent to those skilled in the art from this disclosure that various modifications and variations can be made to the present invention within the scope of the invention, and these modifications and variations are also within the scope of the invention.
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FIG. 1 is a graph showing the effect of the synthetic compound of test example 2 on TRF2 protein expression in HuH-7 cells;
FIG. 2 shows the effect of 5a04 at various concentrations on the expression of various DNA damage related proteins from HuH-7 cells in test example 2.
Detailed Description
The invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention.
Example 1 preparation of 2, 4-dimethoxy-6- (methoxymethoxy) benzaldehyde (Compound 2 a)
In a 100mL round bottom flask, 2-hydroxy-4, 6-dimethoxybenzaldehyde 1a (25 g,0.14 mol) was dissolved in 50mL anhydrous tetrahydrofuran, and after ice-bath cooling, 60% sodium hydride (8.2 g,0.21 mol) was slowly added to the system. After stirring in ice bath for 20 minutes, chloromethyl methyl ether (16.5 g,0.21 mol) was slowly added to the system again to monitor the progress of the reaction by thin layer chromatography, and after the completion of the reaction, 50mL of distilled water was added to the reaction system to terminate the reaction. The mixture was extracted with ethyl acetate, and the organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and dried under reduced pressure and passed through a column to give the desired product 2a 42.7g in 90% yield.
Example 2 preparation of 1- (2, 4-dimethoxy-6- (methoxymethoxy) phenyl) ethanol (Compound 3 a)
2a (10 g,0.044 mol) was dissolved in 50mL anhydrous tetrahydrofuran in a 100mL round bottom flask under nitrogen protection at-78℃and after stirring for 15 min, methyl magnesium bromide (15.36 mL,0.22 mol) was slowly added to the system. After 2 hours, 50mL of saturated ammonium chloride solution was added to the reaction system to terminate the reaction. Extraction with ethyl acetate was continued, and the organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and dried under reduced pressure and passed through a column to give the desired product 3a9.68g in 91.3% yield.
Example 3 preparation of 1- (2, 4-dimethoxy-6- (methoxymethoxy) phenyl) ethanone (Compound 4 a)
1- (2, 4-dimethoxy-6- (methoxymethoxy) phenyl) ethanol 3a (20 g,0.083 mol) was dissolved in 50mL of anhydrous tetrahydrofuran in a 100mL round-bottom flask, and active manganese dioxide (35.88 g, 0.418 mol) was slowly added to the reaction system, followed by reaction at room temperature overnight. Monitoring the reaction progress by thin layer chromatography, filtering the reaction system to remove a filter cake after the reaction is finished, and performing spin-drying on the filtrate under reduced pressure to obtain a target product with a yield of 4a.14.0 g and a yield of 70%.
Examples 4 to 27 Synthesis methods for preparing chalcone analogues 5a1 to 5a26 (5 a1 is taken as an example)
1- (2, 4-dimethoxy-6- (methoxymethoxy) phenyl) ethanone (0.1 g,0.42 mmol) (4 a) and 0.056g (0.42 mmol) of 4-methoxybenzaldehyde were dissolved in 10mL of ethanol, 3mL of 20% sodium hydroxide (NaOH) was slowly dropped under stirring, and the reaction system was stirred at room temperature overnight. After the reaction was completed, an excessive amount of ice water was added to the system until a yellow precipitate was precipitated. Suction filtration is carried out, and filter cakes are dried after being washed by a small amount of ice water. The filter cake was dissolved in 5mL of methanol (MeOH)/Tetrahydrofuran (THF) =1: 1, 0.5mL of 1.0mol/L hydrochloric acid is slowly dripped into the mixed solvent at room temperature, the reaction lasts for 1h, and after the reaction is finished, ice water is added into the reaction solution until yellow precipitate is precipitated. Filtering, washing the filter cake with ice water, and draining. The residue was further recrystallized from ethanol to give 5a 1.132 g of a yellow target product in a yield of 56.4%.
The synthetic reaction routes, yields, physicochemical properties and spectroscopic data for the 26 target compounds are as follows:
reagents and reaction conditions (a) NaH, MOMCl, THF, rt,6h,90%; (b) MeMgBr, THF, -78 ℃,2h,91.3%; (c) MnO (MnO) 2 ,THF,rt,16h,70；(d)various benzaldehydes,NaOH,EtOH-H 2 O(v:v,3:1),rt,8-10h；4N-HCl,MeOH,rt,1-2h,35-73％.
TABLE 1 yields and characterization data for target compounds 5a 1-5 a26
Compound 2a
1 H-NMR(500MHz,CDCl 3 )δ(ppm):10.37(s,1H),6.33(s,1H),6.14(s,1H),5.26(s,2H),3.88(s,3H,-OCH 3 ),3.86(s,3H,-OCH 3 ),3.51(s,3H,-OCH 3 )
Compound 3a
1 H-NMR(500MHz,CDCl 3 )δ(ppm):6.40(d,J＝2.2Hz,1H),6.23(d,J＝2.2Hz,1H),5.24(s,2H),3.87(s,3H),3.83(s,3H),3.53(s,3H),1.54(d,J＝6.7Hz,3H)
Compound 4a
1 H-NMR(500MHz,CDCl 3 )δ(ppm):6.33(s,1H),6.16(s,1H),5.15(s,2H),3.81(s,3H),3.79(s,3H),3.47(s,3H),2.48(s,3H).
Compound 5a1
1 H-NMR(500MHz,CDCl 3 )δ(ppm):14.45(s,1H),7.85(s,1H),7.62(d,J＝8.7Hz,2H),6.98(d,J＝8.7Hz,2H),6.16(d,J＝2.3Hz,1H),6.01(d,J＝2.3Hz,1H),3.97(s,3H),3.90(d,J＝4.3Hz,3H),3.89(s,3H). 13 C-NMR(125MHz,CDCl 3 )δ(ppm):192.22,167.85,165.76,162.61,161.26,142.44,129.95×2,127.84,124.73,116.39×2,105.92,94.09,91.69,54.48×3.
Compound 5a2
(E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(4-nitrophenyl)prop-2-en-1-one(2)Yellow solid. 1 H-NMR(500MHz,acetone-d6)δ(ppm):14.61(s,1H),8.21(d,J＝15.0Hz,1H),8.09(d,J＝15.2Hz,1H),7.91(s,2H),7.67(d,J＝24.2Hz,4H),6.45(d,J＝2.2Hz,1H),6.31(d,J＝2.4Hz,1H),4.22(s,3H),4.14(s,3H). 13 C-NMR(125MHz,CDCl 3 )δ(ppm):193.27,168.41,166.27,162.62,142.32,135.62,130.26×2,128.87×2,128.36,127.58,106.32,93.85,91.30,55.87,55.59.
Compound 5a3
(E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-phenylprop-2-en-1-one(3)Yellow solid. 1 H-NMR(500MHz,CDCl 3 )δ(ppm):14.34(s,1H),7.94(s,1H),7.85(s,1H),7.66(d,J＝7.7Hz,2H),7.45(d,J＝6.3Hz,3H),6.16(d,J＝2.1Hz,1H),6.02(d,J＝2.1Hz,1H),3.97(s,3H),3.89(s,3H), 13 C-NMR(125MHz,CDCl 3 )δ(ppm):192.38,168.25,166.83,162.53,140.76,135.97,132.06,129.47,129.18×2,128.52,128.15,106.44,93.97,91.39,55.92,55.63.
Compound 5a4
(E)-3-(3-bromophenyl)-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one(4)Light yellow solid. 1 H-NMR(500MHz,acetone-d 6 )δ(ppm):14.11(s,1H),7.84(s,1H),7.72(s,1H),7.68(s,1H),7.50(d,J＝7.0Hz,2H),7.28(d,J＝7.8Hz,1H),6.09(d,J＝2.3Hz,1H),5.96(d,J＝2.2Hz,1H). 13 C-NMR(125MHz,CDCl 3 )δ(ppm):192.22,168.45,166.43,162.61,140.28,137.55,132.70,131.02,130.35,128.97,126.97,122.99,106.32,93.42,91.35,55.94,55.61.
Compound 5a5
(E)-3-(3,5-dimethoxyphenyl)-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one(5)light yellow solid. 1 H-NMR(500MHz,CDCl 3 )δ(ppm):14.32(s,1H),7.87(s,1H),7.75(s,1H),6.80(d,J＝2.2Hz,3H),6.55(s,1H),6.15(d,J＝2.3Hz,1H),6.00(d,J＝2.3Hz,1H),3.95(s,3H),3.88(s,9H), 13 C-NMR(125MHz,CDCl 3 )δ(ppm):190.79,168.24,166.18,161.47,152.66,148.56,137.17,129.74,128.90,124.15,119.72,113.67,106.08,93.65,91.16,61.56,55.88,55.84,55.60.
Compound 5a6
(E)-3-(3-bromo-4-methoxyphenyl)-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one(6)yellow solid. 1 H-NMR(500MHz,acetone-d 6 )δ(ppm):14.36(s,1H),7.86(d,J＝2.0Hz,1H),7.80(s,1H),7.74(s,1H),7.54(d,J＝8.5Hz,1H),6.97(s,1H),6.15(d,J＝2.3Hz,1H),6.00(d,J＝2.3Hz,1H),3.98(s,3H),3.97(s,3H),3.88(s,3H). 13 C-NMR(125MHz,acetone-d 6 )δ(ppm):192.26,167.84,162.32,157.77,140.62,133.38×2,129.57,126.47,112.20×2,111.88,106.32,94.83,90.64,56.47,55.91,55.57.
Compound 5a7
(E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(5-methylthiophen-2-yl)prop-2-en-1-one(7)yellow solid. 1 H-NMR(500MHz,CDCl 3 )δ(ppm):14.35(s,1H),7.85(s,1H),7.61(s,1H),7.12(d,J＝3.3Hz,1H),6.74(d,J＝2.9Hz,1H),6.10(d,J＝2.1Hz,1H),5.97(d,J＝2.1Hz,1H),3.97(s,3H),3.79(s,3H),2.52(s,3H). 13 C-NMR(125MHz,CDCl 3 )δ(ppm):191.94,168.38,166.12,163.37,143.97,139.65,135.69,131.67,126.77,125.40,106.26,94.10,90.95,55.78,55.56,15.87.
Chemical combinationObject 5a8
(E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(thiophen-2-yl)prop-2-en-1-one(8)yellow solid. 1 H-NMR(500MHz,CDCl 3 )δ(ppm):14.41(s,1H),7.91(s,1H),7.74(s,1H),7.35(d,J＝14.6Hz,2H),7.04(d,J＝12.7Hz,1H),6.14(d,J＝2.3Hz,1H),5.99(d,J＝2.2Hz,1H),3.91(s,3H),3.84(s,3H). 13 C-NMR(125MHz,CDCl 3 )δ(ppm):191.85,168.21,167.06,162.62,141.07,134.80,131.66,128.27,128.21,126.54,108.28,93.83,91.27,56.19,55.59.
Compound 5a9
(E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(2,4,6-trimethoxyphenyl)prop-2-en-1-one(9)yellow solid.Yellow solid,56.3％yield,m.p:146.3-149℃. 1 H-NMR(500MHz,CDCl 3 )δ(ppm):8.35(s,1H),8.31(s,1H),6.18(s,2H),6.14(d,J＝2.3Hz,1H),5.99(d,J＝2.3Hz,1H),3.95(s,6H),3.94(s,3H),3.90(s,3H),3.87(s,3H 3 ). 13 C-NMR(125MHz,CDCl 3 )δ(ppm):194.07,168.28,165.48,162.94,162.45×2,161.64,134.35,126.75,106.98,106.68,93.73,91.03,90.51×2,55.74,55.56,55.51×2,55.34.
Compound 5a10
(E)-3-(2,3-dimethoxyphenyl)-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one(10)yellow solid. 1 H-NMR(500MHz,CDCl 3 )δ(ppm):14.40(s,1H),8.10(s,1H),8.03(s,1H),7.30(d,J＝8.5Hz,1H),7.13(d,J＝15.5Hz,1H),6.99(d,J＝8.1Hz,1H),6.14(d,J＝2.3Hz,1H),6.00(d,J＝2.3Hz,1H),3.95(s,3H),3.94(s,6H),3.88(s,3H). 13 C-NMR(125MHz,CDCl 3 )δ(ppm):192.93,168.40,165.74,162.56,153.24,137.57,130.25,128.94,124.11,120.56,114.66,106.46,93.83,92.00,61.42,55.90,55.83,55.56.
Compound 5a11
(E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(3-nitrophenyl)prop-2-en-1-one(11)yellow solid. 1 H-NMR(500MHz,CDCl 3 )δ(ppm):14.43(s,1H),8.74(s,1H),8.51(s,1H),8.26(d,J＝11.8Hz,1H),8.15(s,1H),8.03(d,J＝12.5Hz,1H),7.90(d,J＝17.4Hz,1H),6.43(d,J＝2.3.Hz,1H),6.28(d,J＝2.1Hz,1H),4.23(s,3H),4.13(s,3H), 13 C-NMR(125MHz,CDCl 3 )δ(ppm):192.90,168.55,166.74,162.31,138.80,134.13,130.57,129.91,124.10,122.20,93.91,91.45,56.03,55.68.
Compound 5a12
(E)-3-(4-chlorophenyl)-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one(12)yellow solid. 1 H-NMR(500MHz,CDCl 3 )δ(ppm):14.24(s,1H),7.85(s,1H),7.73(s,1H),7.53(d,J＝8.1Hz,2H),7.37(d,J＝8.1Hz,2H),6.13(d,J＝2.2Hz,1H),5.95(d,J＝2.2Hz,1H),3.92(s,3H),3.84(s,3H). 13 C-NMR(125MHz,CDCl 3 )δ(ppm):192.91,168.89,166.39,162.50,141.45,135.18,134.14×2,129.47×2,129.16×2,128.17,106.62,94.10,55.85×2.
Compound 5a13
(E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(pyridin-4-yl)prop-2-en-1-one(13)yellow solid. 1 H-NMR(500MHz,acetone-d 6 )δ(ppm):14.42(s,1H),7.86(d,J＝15.2Hz,1H),7.62(d,J＝15.2Hz,1H),7.26(s,1H),7.12(d,J＝3.1Hz,1H),6.73(s,1H),6.10(d,J＝2.3Hz,1H),5.95(d,J＝2.3Hz,1H),3.91(s,3H),3.83(s,3H), 13 C-NMR(125MHz,CDCl 3 )δ(ppm):191.95,168.52,166.11,162.99,144.20,139.65,135.69,132.34,126.44×2,125.18,94.08,91.33×2,55.81×2,15.48.
Compound 5a14
(E)-3-(4-(diethylamino)phenyl)-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one(14)yellow solid. 1 H-NMR(500MHz,CDCl 3 )δ(ppm):14.72(s,1H),7.81(s,1H),7.76(s,1H),7.51(d,J＝4.6Hz,2H),6.66(d,J＝2.6Hz,2H),6.12(d,J＝2.1Hz,1H),6.12(d,J＝2.1Hz,1H),3.91(s,3H),3.83(s,3H),3.54–3.30(m,4H),1.32–1.14(m,6H), 13 C-NMR(125MHz,CDCl 3 )δ(ppm):192.43,168.29,162.38,130.69,111.33,106.51,93.85,91.14,55.95,55.49,44.52,12.60.
Compound 5a15
(E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(5-methylpyridin-2-yl)prop-2-en-1-one(15)yellow solid. 1 H-NMR(500MHz,CDCl 3 )δ(ppm):14.39(s,1H),7.88(s,1H),7.64(s,1H),7.12(d,J＝3.1Hz,1H),6.73(d,J＝2.2Hz,1H),6.10(d,J＝2.1Hz,1H),3.91(s,3H),3.83(s,3H,),2.52(s,3H), 13 C-NMR(125MHz,CDCl 3 )δ(ppm):191.95,168.37,166.05,162.45,143.96,139.32,135.85,132.19,127.09,125.18,106.31,93.82,89.91,55.81,55.49,16.22.
Compound 5a16
(E)-3-(4-hydroxy-2-methoxyphenyl)-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one(16)yellow solid. 1 H-NMR(500MHz,CDCl 3 )δ(ppm):14.63(s,1H),8.12(s,1H),7.95(s,1H),7.52(d,J＝8.2Hz,1H),6.52(d,J＝8.2Hz,1H),6.48(s,1H),6.15(d,J＝2.3Hz,1H),6.00(d,J＝2.3Hz,1H),5.80(s,1H),3.95(s,3H)3.89(s,3H),3.87(s,3H), 13 C-NMR(125MHz,DMSO-d 6 )δ(ppm):192.05,165.85,165.45,150.30,146.85,143.07,127.70,124.62,121.90,113.90,112.15,106.20×2,93.99,91.14×2,56.14,55.61.
Compound 5a17
(E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(2,3,4-trimethoxyphenyl)prop-2-en-1-one(17)yellow solid. 1 H-NMR(500MHz,CDCl 3 )δ(ppm):14.24(s,1H,Ar-OH),7.86(d,J＝15.5Hz,1H),7.71(d,J＝13.6Hz,1H),7.53(s,1H),7.38(s,1H),6.14(d,J＝2.2Hz,1H),5.99(d,J＝2.2Hz,1H),3.91(s,6H),3.84(s,6H), 13 C-NMR(125MHz,CDCl 3 )δ(ppm):191.85,168.03,166.81,162.50,156.40,153.62,140.38,136.94,134.13×2,129.95,129.14,128.09,106.99,93.87,91.34,61.40,60.90,56.07,55.82.
Compound 5a18
(E)-3-(2-bromo-5-chlorophenyl)-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one(18)yellow solid. 1 H-NMR(500MHz,CDCl 3 )δ(ppm):14.14(s,1H),8.00(s,1H),7.84(s,1H),7.66(d,J＝2.4Hz,1H),7.59(s,1H),7.24(dd,J＝8.5,2.5Hz,1H),6.16(d,J＝2.3Hz,1H),6.01(d,J＝2.3Hz,1H),3.97(s,3H),3.89(s,3H), 13 C-NMR(125MHz,CDCl 3 )δ(ppm):190.86,167.88,165.79,161.98,137.84,136.33,133.79,132.36,130.30,129.26,126.87,122.40,105.30,92.91,90.39,55.15,54.62.
Compound 5a19
(E)-3-(3-bromo-4-hydroxyphenyl)-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one(19),yellow solid. 1 H-NMR(500MHz,acetone-d 6 )δ(ppm):14.32(s,1H,Ar-OH),9.49(s,1H),7.90(d,J＝2.0Hz,1H),7.88(s,1H),7.73(s,1H),7.64(dd,J＝8.4,2.0Hz,2H),7.12(s,1H),6.13(d,J＝2.3Hz,1H),6.11(d,J＝2.3Hz,1H),4.02(s,3H,-OCH 3 ),3.89(s,3H,-OCH 3 ), 1 H-NMR(500MHz,acetone-d 6 )δ(ppm):193.19,169.10,167.46,163.74,156.82,141.73,134.29×2,129.90,126.76,117.73,111.06,106.92,94.76,91.84,56.55,56.08.ESI-MS m/z:381.02(M+H) + ,calcd forC17H15BrO5:379.20
Compound 5a20
(E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one(20),yellow solid. 1 H-NMR(500MHz,CDCl 3 )δ(ppm):8.34(s,1H),8.31(s,1H),6.18(s,2H),6.15(d,J＝2.3Hz,1H),6.00(d,J＝2.3Hz,1H),3.95(s,6H,-OCH 3 ),3.95(s,3H,-OCH 3 ),3.91(s,3H),3.87(s,3H,-OCH 3 ), 13 C-NMR(125MHz,CDCl 3 )δ(ppm):192.92,168.48,166.42,162.53,140.76,135.97,134.19,132.06,129.47,129.18,128.52,128.15,106.39,93.93,91.39,55.92,55.63.
Compound 5a21
(E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(3-hydroxy-4-methoxyphenyl)prop-2-en-1-one(21)light Yellow solid. 1 H-NMR(500MHz,CDCl 3 )δ(ppm):14.36(s,1H,Ar-OH),7.86(s,1H),7.80(s,1H),7.74(s,1H),7.55(d,J＝2.0Hz,1H),6.97(s,1H),6.96(d,J＝8.5Hz,1H),6.15(d,J＝2.3Hz,1H),6.00(d,J＝2.3Hz,1H),3.98(s,3H,-OCH 3 ),3.97(s,3H,-OCH 3 ),3.88(s,3H,-OCH 3 ), 13 C-NMR(125MHz,CDCl 3 )δ(ppm):193.98,162.50,158.83,156.43,142.18,137.26,132.93,131.08,130.35,130.28,126.79,123.02,,94.84,93.59,92.52,56.31,55.95,55.54.
Compound 5a22
(E)-3-(2-bromo-5-fluorophenyl)-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one(22)yellow solid. 1 H-NMR(500MHz,CDCl 3 )δ(ppm):10.29(s,1H),7.80(s,1H),6.71(d,J＝8.6Hz,1H),6.63(s,1H),6.50(d,J＝2.1Hz,1H),6.47(d,J＝2.1Hz,1H),3.90(s,3H,-OCH 3 ),3.88(s,3H,-OCH 3 ), 13 C-NMR(125MHz,CDCl 3 )δ(ppm):190.20,167.52,165.79,161.51,137.84,136.33,133.44 132.69,130.41,129.56,126.71,122.40,105.30,92.91,90.39,54.97,54.49.
Compound 5a23
(E)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one(23)yellow solid. 1 H-NMR(500MHz,CDCl 3 )δ(ppm):14.43(s,1H,7.79(s,1H),7.76(s,1H),7.18(d,J＝1.9Hz,1H),7.15(d,J＝1.9Hz,1H),6.93(s,1H),6.14(d,J＝2.3Hz,1H),6.00(d,J＝2.3Hz,1H),4.33(t,J＝4.0Hz,4H),3.95(s,3H,-OCH 3 ),3.95(s,3H,-OCH 3 ) 13 C-NMR(125MHz,CDCl 3 )δ(ppm):192.54,168.21,166.13,162.49,145.63,144.21,142.28,130.24,125.78,122.28,116.83,106.32,93.96,91.07,64.69,64.26,55.86,55.62.
Compound 5a24
(E)-3-(3-chlorophenyl)-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one.Yellow solid,54.87％yield,m.p:92.6–94.2℃. 1 H NMR(500MHz,CDCl 3 )δ(ppm):14.12(s,1H),7.80(d,J＝15.6Hz,1H),7.61(d,J＝15.6Hz,1H),7.50(s,1H),7.28(s,1H),7.39(d,J＝6.63Hz,1H),7.19(s,1H),6.04(d,J＝2.30Hz,1H),5.90(d,J＝2.29Hz,1H),3.85(s,3H),3.77(s,3H). 13 CNMR(150MHz,CDCl 3 )δ(ppm):192.26,168.44,166.46,162.51,140.42,137.48,134.84,130.09,128.90,128.25,127.86,126.59,106.30,93.84,91.34,55.93,55.61.ESI-MS m/z:319.10(M+H) + ,calcd for C 17 H 15 ClO 4 :318.01
Compound 5a25
(E)-3-(3-fluorophenyl)-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one.Yellow solid,70.59％yield,m.p:104.1–105.8℃. 1 H NMR(500MHz,CDCl 3 )δ(ppm):14.26(s,1H),7.92(d,J＝15.59Hz,1H),7.76(d,J＝15.59Hz,1H),7.41(s,1H),7.40(s,1H),7.34(d,J＝11.40Hz,1H),7.13(ddd,J＝2.55,5.23,8.44Hz,1H),6.16(d,J＝2.35Hz,1H),6.02(d,J＝2.33Hz,1H),3.97(s,3H),3.89(s,3H). 13 C NMR(150MHz,CDCl 3 )δ(ppm):192.18,168.49,166.56,162.53,140.05,136.49,131.35,130.13,129.45,129.39,126.26,124.57,106.32,93.92,91.40,55.89,55.61.ESI-MS m/z:303.10(M+H) + ,calcd for C 17 H 15 FO 4 :302.10
Compound 5a26
(E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(3-(trifluoromethyl)phenyl)prop-2-en-1-one.Yellow solid,65.83％yield,m.p:118.2–120.0℃. 1 H NMR(500MHz,CDCl 3 )δ(ppm):14.12(s,1H),7.79(m,1H),7.63(m,1H),7.29(d,J＝7.87Hz,1H),7.28(s,J＝4.78Hz,1H),7.20(s,1H),7.00(m,1H),6.03(d,J＝2.21Hz,1H),5.89(d,J＝2.20Hz,1H),3.85(s,3H),3.76(s,3H). 13 C NMR(150MHz,CDCl 3 )δ(ppm):192.32,168.43,166.46,162.58,140.62,137.91,134.84,130.34,128.86,124.45,116.87,114.31,114.14,106.33,93.88,91.34,55.90,55.59.ESI-MS m/z:353.10(M+H) + ,calcd for C 18 H 15 F 3 O 4 :352.10.
Test example 1 Compounds inhibit proliferation of liver cancer cells
In this test example, the effect of the synthesized compound in inhibiting liver tumor cell proliferation is illustrated by using human liver cancer cell lines Huh-7d, hepG2 and SMMC7721, but it is understood that the use of the synthesized compound in preparing anti-liver tumor drugs is illustrated by using only human liver cancer cell lines Huh-7d, hepG2 and SMMC7721, but the human liver tumor cell lines Huh-7d, hepG2 and SMMC7721 and the like are included in the invention. Experiments prove that 5a04 has remarkable effects on various human liver tumor cells including but not limited to human liver cancer cell lines Huh-7d, hepG2, SMMC7721 and the likeInhibiting proliferation of tumor cells. Human hepatoma cell lines Huh-7d, hepG2 and SMMC7721 were inoculated into 96-well plates, respectively, the inoculation density was 5000 cells/160. Mu.L/well, after 6 hours of attachment of the cells, 40. Mu.L of a medium containing the corresponding concentration of the compound (chalcone derivative) or an equal volume of a medium containing 0.1% DMSO was added. Incubation was continued for 48h, after which MTT (5 mg/ml) was added and incubation was continued for 4h, and the culture was terminated, taking care to remove the culture supernatant in the wells. 100ul DMSO was added to each well and the mixture was shaken for 10 minutes to allow the crystals to fully thaw. Selecting 490nm wavelength, measuring light absorption value of each hole on ELISA monitor, recording result, and calculating half inhibition concentration IC 50 Values, results are given in the following table:
Table 1.IC 50 (μM)values determined by MTT assay a .
a IC 50 the values represent the concentration of the drug required to inhibit half of the tumor cell viability, the data of this experiment are derived from the results of 3 independent repeated experiments, the treatment mode of the data is standard deviation, and the drug treatment time of this experiment is 48 hours.
Test example 2 Effect of Compounds on TRF2 expression in vitro cultured Huh-7d cells
After cell attachment, the compound was added and treated for 48h. Discarding the culture medium, washing with pre-cooled PBS once, sucking off PBS, digesting, centrifuging to collect cells every 5×10 5 Each cell was added with 100. Mu.L of 1 Xcell lysate, and the mixture was boiled in boiling water for 10min to denature the protein, and the sample was stored at-20℃to avoid repeated freeze thawing. The prepared gel is arranged in an electrophoresis tank, and then the electrophoresis separation and the film transfer are carried out on the sample. After the transfer of the film is finished, the film is sealed by a sealing liquid containing 5% of skimmed milk powder, and the film is sealed by a shaking table at room temperature for 90min. After the end of the blocking, the milk powder was washed with TBST, the pre-formulated primary antibody was added and incubated overnight in a shaker at 4 ℃. Recovering and washing primary antibody, TBST washing for 7min×3 times, adding secondary antibody (the dilution ratio is l: 2000), and incubating lh at room temperature in shaking tableThe secondary antibody was washed, TBST7 min. Times.3 times, and then developed in ECL developer. The results are shown in FIG. 1.
The results of FIG. 1 show that the expression of TRF2 in HuH-7 cells by the synthetic compounds was detected using the Western-blot method described above. The results show that most of the compounds can reduce the expression level of TRF2 in HuH-7 cells, and particularly that the compound 5a04 can significantly inhibit the expression level of TRF2 in HuH-7 cells, so that the compound 5a04 is a high-efficiency inhibitor of TRF 2.
Further we found that 5a04 at three concentrations of 1. Mu.M, 2. Mu.M and 4. Mu.M reduced the expression of TRF2, RPA and Rad51 proteins in a dose-dependent manner, and the expression level of r-H2AX protein was up-regulated in a dose-dependent manner, and the specific results are shown in FIG. 2.

Claims (3)

1. The application of chalcone analogues in preparing anti-liver cancer drugs is characterized in that the chalcone analogues treat liver cancer by inhibiting the expression of TRF 2;
the chalcone analogues have the following structural formula:
。
2. the use of chalcone analogues according to claim 1, wherein the anti-liver cancer medicament comprises an active ingredient and a pharmaceutical adjuvant, and the active ingredient comprises the chalcone analogues according to claim 1.
3. The use of chalcone analogues according to claim 1, wherein the pharmaceutical preparation of the anti-liver cancer drug is any one of injection, tablet, capsule, aerosol, suppository, film, drop pill, ointment, controlled release agent, sustained release agent or nano preparation.
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