CN111269104A - Chalcone analogue and application thereof - Google Patents
Chalcone analogue and application thereof Download PDFInfo
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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), wherein R is selected from substituted or unsubstituted aryl or heteroaryl; the substituent on the aryl or the heteroaryl is selected from C1～C5Alkyl radical, C1～C5Alkoxy, halogen or trifluoromethyl. In vitro anti-tumor activity test results show that most of the chalcone analogues have high anti-tumor activity.
Description
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to a chalcone analogue and application thereof.
Background
Telomeres are special structures at the tail end of linear chromosomes of eukaryotic cells and have the functions of protecting the tail end of chromosomes and maintaining the stability of genomes. Telomeres at the ends of linear chromosomes can prevent linear chromosome ends from being recognized as DNA damage and inhibit DNA damage response mechanisms. In human cells, telomeres consist of telomeric DNA repeats 5 '-TTAGGG-3' and the telomere-binding protein "Shelterin". The protein complex Shelterin consists of six proteins: POT1(protection software 1), TRF1 (temporal recurring binding factor 1), TRF2 (temporal recurring binding factor 2), TIN2(TRF1-interacting protein 2), TPP1(the POT1-and TIN2-organizing protein), RAP1 (predictor/activator protein) ]. In tissue cells, aberrant expression of certain proteins or dysfunction of certain proteins in the Shelterin complex can disrupt the integrity of telomeres and the stability of their genomes.
TRF2 is a homologue of TRF1 discovered by Broccoli et al in 1997, which can bind directly to telomere duplex DNA and is a specific telomere sequence binding protein. TRF2 has a molecular weight of 66KD, and is composed of 500 amino acids, and the gene is located at 16q 22.1. TRF2 also contains 3 important domains: a basic region at the amino terminus, a dimeric conserved sequence in the middle, and a Myb-type DNA domain at the carboxy terminus. Deletion of TRF2 affects the formation of T-loop, thereby causing chromosome end fusion. In addition, 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 tissues. Therefore, TRF2 can be used as a potential target for treating malignant tumor.
Piperacin B (flavokawain B) is a natural chalcone compound in medicinal plant kava root, and has wide biological activity, such as anti-tumor, anti-oxidation, prevention and treatment of diabetes and its complications, etc. At present, researches on kava-kava at home and abroad mostly focus on the anxiolytic and depressive actions from literature reports, but few research reports on the antitumor activity of the kava-ka. The compound with chalcone structure has various anticancer activities, such as inhibiting tumor proliferation, deterioration and migration. On the basis, the invention provides novel chalcone derivatives of kava-piperin 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, wherein the chalcone analogue has better antitumor activity.
A chalcone analogue has a structure shown in formula (I):
in formula (I), R is selected from various substituted or unsubstituted aryl or heteroaryl; the substituent on the aryl or the heteroaryl is selected from C1～C5Alkyl radical, C1～C5Alkoxy, halogen or trifluoromethyl.
The invention designs a novel chalcone compound by a drug design method on the basis of a kava piperine B structural framework. In vitro anti-tumor activity test results show that most of the chalcone analogues have high anti-tumor activity.
Preferably, the aryl group is phenyl; the heteroaryl is thienyl, pyrimidinyl or 2, 3-dihydrobenzo [ b ] [1, 4] dioxinyl.
Preferably, the substituents on the aryl or heteroaryl group are selected from methyl, ethyl, N-dimethylamino, halogen, methoxy.
Preferably, R is selected from the following groups:
the invention also provides an application of the chalcone analogue, and the chalcone analogue is used for preparing an anti-tumor medicament.
Preferably, the chalcone analogs treat tumors and tumor-related diseases 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, esophageal cancer, gallbladder 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 lymphocytic 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 myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome, and promyelocytic leukemia; multiple myeloma; tumors of mesenchymal origin, including fibroma and rhabdomyosarcoma; other tumors, including melanoma, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, keratoxanthoma, thyroid carcinoma and Kaposi's sarcoma.
Most preferably, the chalcone analogs have the following structural formula:
the activity test shows that the compound has the best antitumor activity.
The invention also provides a pharmaceutical preparation which comprises an effective component and a pharmaceutic adjuvant, wherein the effective component comprises the chalcone analogue.
Preferably, the pharmaceutical preparation is any one of injection, tablet, capsule, aerosol, suppository, membrane, dripping pill, ointment, controlled release agent, sustained release agent or nano preparation.
Compared with the prior art, the invention has the following beneficial effects: based on the kava piperine B structural framework, the novel chalcone compound is designed and synthesized by a drug design method. The compound has excellent cell proliferation inhibiting effect of TRF2 overexpression or abnormal activation and excellent specific or broad-spectrum inhibiting effect of TRF2 kinase, has excellent inhibiting effect on drug-resistant mutant strains, and can effectively treat tumors.
For the purpose of facilitating understanding, the invention will be described in detail below with reference to specific drawings and examples. It is specifically intended that the specification and drawings be considered as exemplary only, and not as limiting the scope of the invention. It will be apparent to those skilled in the art from this disclosure that various modifications and variations can be made in the present invention within the scope of the invention, which is also encompassed by the invention.
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FIG. 1 is a graph showing the effect of the synthetic compound in test example 2 on TRF2 protein expression in HuH-7 cells;
FIG. 2 is a graph showing the effect of 5a04 on the expression of various DNA damage-related proteins in HuH-7 cells at various concentrations in test example 2.
Detailed Description
The present 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 2a)
In a 100mL round-bottomed flask, 2-hydroxy-4, 6-dimethoxybenzaldehyde 1a (25g,0.14mol) was dissolved in 50mL of anhydrous tetrahydrofuran, and after cooling in an ice bath, 60% sodium hydride (8.2g,0.21mol) was slowly added to the system. After stirring in ice bath for 20 minutes, chloromethyl methyl ether (16.5g,0.21mol) was slowly added to the system to monitor the progress of the reaction by thin layer chromatography, and after the reaction was completed, 50mL of distilled water was added to the reaction system to terminate the reaction. The extraction was continued with ethyl acetate, and the organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and spin-dried under reduced pressure to obtain the desired product 2a 42.7g, yield 90%.
EXAMPLE 2 preparation of 1- (2, 4-dimethoxy-6- (methoxymethoxy) phenyl) ethanol (Compound 3a)
2a (10g,0.044mol) was dissolved in 50mL of anhydrous tetrahydrofuran in a 100mL round-bottom flask at-78 ℃ under nitrogen, and after stirring for 15 minutes, methylmagnesium bromide (15.36mL,0.22mol) was slowly added to the system. After 2 hours, 50mL of a saturated ammonium chloride solution was added to the reaction system to terminate the reaction. The extraction was continued with ethyl acetate, and the organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and spin-dried under reduced pressure to obtain the desired product 3a9.68g in 91.3% yield.
EXAMPLE 3 preparation of 1- (2, 4-dimethoxy-6- (methoxymethoxy) phenyl) ethanone (Compound 4a)
In a 100mL round-bottomed flask, 1- (2, 4-dimethoxy-6- (methoxymethoxy) phenyl) ethanol 3a (20g,0.083mol) was dissolved in 50mL of anhydrous tetrahydrofuran, and after active manganese dioxide (35.88g,0.415mol) was slowly added to the reaction system, the reaction was allowed to proceed at room temperature overnight. Monitoring the reaction process by thin-layer chromatography, after the reaction is finished, pumping the reaction system to remove filter cakes, and carrying out reduced pressure spin-drying on the filtrate to obtain the target product 4a 14.0g with the yield of 70%.
Examples 4 to 27 general synthetic methods for the preparation of chalcone analogs 5a1 to 5a26 (example 5a 1)
1- (2, 4-dimethoxy-6- (methoxymethoxy) phenyl) ethanone (0.1g, 0.42mmol) (4a) and 0.056g (0.42mmol) of 4-methoxybenzaldehyde were dissolved in 10mL of ethanol, 3mL of 20% sodium hydroxide (NaOH) was slowly dropped while stirring, and the reaction system was stirred at room temperature overnight. After the reaction was completed, an excess amount of ice water was added to the system until a yellow precipitate was precipitated. Suction filtration is carried out, and a filter cake is washed by a small amount of ice water and then is drained. The filter cake was dissolved in 5mL methanol (MeOH)/Tetrahydrofuran (THF) ═ 1: 1, 0.5mL of 1.0mol/L hydrochloric acid was slowly dropped into the mixed solvent at room temperature, the reaction was continued for 1 hour, and after the completion of the reaction, ice water was added to the reaction solution until a yellow precipitate was precipitated. And (4) pumping filtration, washing a filter cake with ice water, and pumping to dry. The residue was further recrystallized from ethanol to give 5a 10.132g of a yellow target product in a yield of 56.4%.
The reaction route, yield, physicochemical properties and spectral data of the 26 target compounds synthesized were as follows:
reaction reagents and reaction conditions (a) NaH, MOMCl, THF, rt,6h, 90%; (b) MeMgBr, THF, -78 deg.C, 2h, 91.3%; (c) MnO2,THF,rt,16h,70；(d)various benzaldehydes,NaOH,EtOH-H2O(v:v,3:1),rt,8-10h；4N-HCl,MeOH,rt,1-2h,35-73％.
TABLE 1 yield and characterization data for target compounds 5a 1-5 a26
Compound 2a
1H-NMR(500MHz,CDCl3)δ(ppm):10.37(s,1H),6.33(s,1H),6.14(s,1H),5.26(s,2H),3.88(s,3H,-OCH3),3.86(s,3H,-OCH3),3.51(s,3H,-OCH3)
Compound 3a
1H-NMR(500MHz,CDCl3)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
1H-NMR(500MHz,CDCl3)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
1H-NMR(500MHz,CDCl3)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).13C-NMR(125MHz,CDCl3)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.1H-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).13C-NMR(125MHz,CDCl3)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.1H-NMR(500MHz,CDCl3)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),13C-NMR(125MHz,CDCl3)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.1H-NMR(500MHz,acetone-d6)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).13C-NMR(125MHz,CDCl3)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.1H-NMR(500MHz,CDCl3)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),13C-NMR(125MHz,CDCl3)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.1H-NMR(500MHz,acetone-d6)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).13C-NMR(125MHz,acetone-d6)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.1H-NMR(500MHz,CDCl3)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).13C-NMR(125MHz,CDCl3)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.
Compound 5a8
(E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(thiophen-2-yl)prop-2-en-1-one(8)yellow solid.1H-NMR(500MHz,CDCl3)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).13C-NMR(125MHz,CDCl3)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℃.1H-NMR(500MHz,CDCl3)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,3H3).13C-NMR(125MHz,CDCl3)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.1H-NMR(500MHz,CDCl3)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).13C-NMR(125MHz,CDCl3)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.1H-NMR(500MHz,CDCl3)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),13C-NMR(125MHz,CDCl3)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.1H-NMR(500MHz,CDCl3)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).13C-NMR(125MHz,CDCl3)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.1H-NMR(500MHz,acetone-d6)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),13C-NMR(125MHz,CDCl3)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.1H-NMR(500MHz,CDCl3)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),13C-NMR(125MHz,CDCl3)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.1H-NMR(500MHz,CDCl3)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),13C-NMR(125MHz,CDCl3)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.1H-NMR(500MHz,CDCl3)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),13C-NMR(125MHz,DMSO-d6)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.1H-NMR(500MHz,CDCl3)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),13C-NMR(125MHz,CDCl3)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.1H-NMR(500MHz,CDCl3)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),13C-NMR(125MHz,CDCl3)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.1H-NMR(500MHz,acetone-d6)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,-OCH3),3.89(s,3H,-OCH3),1H-NMR(500MHz,acetone-d6)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.1H-NMR(500MHz,CDCl3)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,-OCH3),3.95(s,3H,-OCH3),3.91(s,3H),3.87(s,3H,-OCH3),13C-NMR(125MHz,CDCl3)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.1H-NMR(500MHz,CDCl3)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,-OCH3),3.97(s,3H,-OCH3),3.88(s,3H,-OCH3),13C-NMR(125MHz,CDCl3)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.1H-NMR(500MHz,CDCl3)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,-OCH3),3.88(s,3H,-OCH3),13C-NMR(125MHz,CDCl3)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.1H-NMR(500MHz,CDCl3)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,-OCH3),3.95(s,3H,-OCH3)13C-NMR(125MHz,CDCl3)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℃.1H NMR(500MHz,CDCl3)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).13CNMR(150MHz,CDCl3)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 C17H15ClO4:318.01
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℃.1H NMR(500MHz,CDCl3)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).13C NMR(150MHz,CDCl3)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 forC17H15FO4:302.10
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℃.1H NMR(500MHz,CDCl3)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).13C NMR(150MHz,CDCl3)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 C18H15F3O4:352.10.
Test example 1 Compounds inhibit proliferation of hepatoma cells
In the testIn the examples, the effect of the synthesized compounds in inhibiting the proliferation of liver tumor cells is illustrated by using human liver cancer cell strains Huh-7d, HepG2 and SMMC7721 as examples, but it should be understood that, although the use of the synthesized compounds in preparing anti-liver tumor drugs is illustrated by using human liver cancer cell strains Huh-7d, HepG2 and SMMC7721 as examples, the "human liver tumor" cells in the invention include, but are not limited to, human liver cancer cell strains Huh-7d, HepG2 and SMMC 7721. Experiments prove that 5a04 has obvious effect of inhibiting the proliferation of tumor cells for various human liver tumor cells including but not limited to human liver cancer cell strains Huh-7d, HepG2, SMMC7721 and the like. The human liver cancer cell strains Huh-7d, HepG2 and SMMC7721 are respectively inoculated in a 96-well plate, the inoculation density is 5000 cells/160 mu L/well, after the cells adhere to the wall for 6 hours, 40 mu L of culture medium containing the compound (chalcone derivative) with the corresponding concentration or the equal volume of culture medium containing 0.1% DMSO is added. Incubation was continued for 48h, followed by additional MTT (5mg/ml) for 4h, the culture terminated and the culture supernatant from the wells carefully aspirated. Add 100ul DMSO/well and shake for 10 minutes to fully melt the crystals. Selecting 490nm wavelength, measuring the light absorption value of each pore on an enzyme-linked immunosorbent assay, recording the result, and calculating the median inhibitory concentration IC50Values, results are given in the following table:
Table 1.IC50(μM)values determined by MTT assaya.
aIC50the value represents the drug concentration required for inhibiting half of the tumor cell viability, the data of the experiment is derived from the results of 3 independent repeated experiments, the processing mode of the data is standard deviation, and the drug processing time of the experiment is 48 hours.
Test example 2 Effect of Compounds on TRF2 expression in Huh-7d cells cultured in vitro
When the cells were adherent, compound was added for 48h of treatment. Discarding the medium, washing with pre-cooled PBS, removing PBS by aspiration, digesting, centrifuging, and collecting cells at a rate of 5 × 105Adding 100 μ L of each cellBoiling 1 Xcell lysate in boiling water for 10min to denature protein, and storing the sample at-20 deg.C to avoid repeated freeze thawing. The prepared gel is arranged in an electrophoresis tank, and then the gel is loaded for electrophoretic separation and membrane transfer. And (5) sealing with a sealing solution containing 5% skimmed milk powder after the membrane conversion is finished, and sealing for 90min in a shaking table at room temperature. After blocking, the milk powder was washed with TBST, the pre-formulated primary antibody was added and incubated overnight in a shaker at 4 ℃. The primary antibody was recovered and washed with TBST7min X3 times, secondary antibody (related secondary antibody was prepared according to the instructions for primary antibody, dilution ratio l:2000) was added, incubated lh with shaking at room temperature, secondary antibody washed with TBST7min X3 times, and then developed in ECL developer. The results are shown in FIG. 1.
The results in FIG. 1 show that the expression of TRF2 in HuH-7 cells was examined by the Western-blot method described above for the synthesized compounds. The results show that most of the compounds can reduce the expression level of TRF2 in HuH-7 cells, particularly the compound 5a04 can obviously inhibit the expression level of TRF2 in HuH-7 cells, and the result shows that 5a04 is a high-efficiency inhibitor of TRF 2.
Further we found that 5a04 can dose-dependently decrease the expression of TRF2, RPA and Rad51 protein and dose-dependently up-regulate the expression of r-H2AX protein at three concentrations of 1. mu.M, 2. mu.M and 4. mu.M, and the specific results are shown in FIG. 2.
Claims (10)
1. A chalcone analog having a structure according to formula (I):
in formula (I), R is selected from substituted or unsubstituted aryl or heteroaryl; the substituent on the aryl or the heteroaryl is selected from C1～C5Alkyl radical, C1～C5Alkoxy, halogen or trifluoromethyl.
2. A chalcone analogue according to claim 1, wherein said aryl group is phenyl;
the heteroaryl is thienyl, pyrimidinyl or 2, 3-dihydrobenzo [ b ] [1, 4] dioxinyl.
3. A chalcone analogue according to claim 1 or 2, wherein the substituents on the aryl or heteroaryl group are selected from methyl, ethyl, N-dimethylamino, halogen, methoxy or trifluoromethyl.
4. The chalcone analog according to claim 1, wherein R is selected from the group consisting of:
wherein "-" represents a substitution position.
5. The use of chalcone analogues according to any of the claims 1 to 4, wherein the chalcone analogues are used for the preparation of anti-tumor drugs.
6. The use of chalcone analogues according to claim 5, wherein the chalcone analogues treat tumors and tumor-related diseases by inhibiting the expression of TRF 2.
7. The chalcone analog for use according to claim 6, wherein the tumor-associated disease includes, but is not limited to: cancers such as liver cancer (including small cell lung cancer), bladder cancer, breast cancer, colon cancer, kidney cancer, lung cancer, esophageal cancer, gallbladder 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 lymphocytic 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 myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome, and promyelocytic leukemia; multiple myeloma; tumors of mesenchymal origin, including fibroma and rhabdomyosarcoma; other tumors, including melanoma, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, keratoxanthoma, thyroid carcinoma and Kaposi's sarcoma.
8. The use of a chalcone analog according to claim 5, wherein the chalcone analog has a structural formula as follows:
9. a pharmaceutical preparation comprising an active ingredient and a pharmaceutical excipient, wherein the active ingredient comprises the chalcone analogue according to any one of claims 1 to 4.
10. The pharmaceutical preparation of claim 9, wherein the pharmaceutical preparation is any one of an injection, a tablet, a capsule, an aerosol, a suppository, a membrane, a drop pill, an ointment, a controlled release agent, a sustained release agent, or a nano-preparation.
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