CN111925378B - 5-substituted icaritin derivative and anti-tumor application thereof - Google Patents

5-substituted icaritin derivative and anti-tumor application thereof Download PDF

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CN111925378B
CN111925378B CN202010942598.1A CN202010942598A CN111925378B CN 111925378 B CN111925378 B CN 111925378B CN 202010942598 A CN202010942598 A CN 202010942598A CN 111925378 B CN111925378 B CN 111925378B
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icaritin
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王先恒
赵长阔
何芋岐
崔晗琦
柯希
赵缘财
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Zunyi Medical University
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Abstract

The invention provides a 5-substituted icaritin derivative with a structural formula shown as 4, a preparation method and anti-tumor application thereof.

Description

5-substituted icaritin derivative and anti-tumor application thereof
Technical Field
The invention belongs to the field of new drug design and synthesis, and particularly relates to a novel 5-substituted icaritin derivative and anti-tumor application thereof.
Background
Icaritin (Icaritin,1) is a natural allyl substituted flavone compound extracted from traditional Chinese medicine epimedium, has various pharmacological activities such as anti-tumor and anti-dementia, and is limited in clinical use due to poor solubility and low bioavailability. Icaritin is metabolized in vivo into β -anhydroicaritin (compound 2).
Figure BDA0002674137810000011
Research shows that icaritin has unique antitumor action mechanism, and pharmacologists hope to modify the flavone structure of the icaritin to obtain derivatives with better activity. In order to find anticancer drug candidates with better drug effect and stronger toxicity, a drug molecule is designed and synthesized, and a novel 5-substituted icaritin derivative 4 with a unique structure is obtained by substituting hydroxyl at the 5-position of icaritin by C1-C5 alkyl, haloalkyl, allyl, propargyl and benzyl.
Disclosure of Invention
In one aspect, the present invention provides a novel 5-substituted icaritin derivative; the structural formula is shown as a formula 4,
Figure BDA0002674137810000012
in another aspect, the present invention provides a method for synthesizing the 5-substituted icaritin derivative 4 as described above, comprising: 1) the icaritin 1 and formic acid react in a proper organic solvent to obtain a compound 2, 2), the compound 2 reacts with dimethyl sulfate in acetone in the presence of an alkali catalyst to obtain a compound 3, 3), and the compound 3 reacts with a halogen substituted alkane R-X to obtain a 5-substituted icaritin derivative shown in a formula 4, wherein the synthetic route is shown as follows:
Figure BDA0002674137810000021
in a preferred embodiment, the alkyl halide of step 3) is selected from the group consisting of chlorine, bromine, and iodine, and the alkyl group is selected from the group consisting of C1-C5 alkyl, haloalkyl, allyl, propargyl, and benzyl.
In a preferred embodiment, the alkyl group R-X in step 3) is a halogen-substituted alkyl group, and the halogen X is selected from bromine or iodine.
In a preferred embodiment, the alkyl group of the halogen-substituted alkyl R-X in the step 3) is selected from the group consisting of C1-C3 alkyl, halogenated C1-C3 alkyl and benzyl.
Activity tests prove that the 5-substituted icaritin derivative shown in the formula 4 designed and synthesized by the invention has good anti-tumor effect; especially against liver cancer, colon cancer, lung cancer and breast cancer; the in vitro inhibition rate is as high as 64% -72%, and the inhibition activity is equivalent to that of positive control drugs of camptothecin and tamoxifen; can be used as a novel epimedium flavonoid candidate drug for antitumor clinical application. Therefore, the fourth aspect of the present invention provides the use of the 5-substituted icaritin derivative represented by formula 4 for preparing an antitumor drug; preferably, the application of the compound in preparing medicines for resisting liver cancer, colon cancer, lung cancer and breast cancer.
The invention has the advantages that: a novel epimedium flavone derivative 4 is obtained by introducing alkyl on a 5-position hydroxyl group on an icaritin parent flavone structure. The activity test shows that the derivatives have good antitumor activity, and are especially suitable for tumors such as liver cancer, colon cancer, lung cancer and breast cancer. In addition, the synthesis method of the 5-substituted icaritin derivative 4 has the advantages of easily obtained raw materials, high yield of the synthesis route and easy operation and implementation.
In the above synthesis and preparation method, the organic solvent may also be selected from N, N-dimethylformamide (abbreviated as DMF), dimethyl sulfoxide (abbreviated as DMSO), dichloromethane (abbreviated as DCM), chloroform, acetonitrile, tetrahydrofuran or diethyl ether, depending on the temperature and polarity of the solvent required for the reaction. The reaction temperature may be appropriately selected depending on the type of the reaction. The reaction time can be obtained by tracking the reaction condition through monitoring means such as thin layer chromatography TLC, high performance liquid chromatography HPLC or LC-MS liquid mass spectrum combination and the like.
Detailed Description
The invention will be further illustrated by the following specific examples, which are not intended to limit the scope of the invention. Without departing from the inventive concept, a person skilled in the art may make modifications or combinations of the parameters or conditions of the claims, which modifications or combinations shall also be considered as the protective scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims. The raw materials and reagents of the invention are purchased from the national medicine group; the solvent is sufficient from Zunyi Shuangju chemical Co., Ltd. The reagents used are all chemically pure, unless otherwise specified.
Example 1And preparing beta-anhydroicaritin 2:
a solution of Icaritin (3g, 8.2mmol) in formic acid (50mL) was stirred at reflux for 20 h. The reaction solution was then poured into crushed ice. The solid was collected by filtration to give the title compound (2, 2.8g, 93.3%) as a yellow powder. Melting point: 221 ℃ and 222 ℃ (illumination temperature: 223 ℃, Akai et al, 1935).
1H NMR(400MHz,CHCl3)δ＝11.47(s,1H,5-OH),8.17(d,J＝8.7Hz,2H,Ar-H),7.03(d,J＝8.7Hz,2H,Ar-H),6.64(s,1H,3-OH),6.24(s,1H,Ar-H),3.88(s,3H,CH3O),2.89(t,J＝6.8Hz,2H,CH2-CH2-C(CH3)2),1.88(t,J＝6.8Hz,2H,CH2-CH2-C(CH3)2),1.37(s,6H,(CH3)2).
Example 2Compound 3(R ═ CH)3) The preparation of (1):
compound 2(100mg, 0.27mmol) and K2CO3A solution of (75mg, 0.54mmol) in acetone (2ml) was stirred at room temperature for 10 minutes. Dimethyl sulfate (1equ.) was added dropwise to the suspension over 10 minutes. The reaction was heated to reflux for 6 hours. After cooling to room temperature, the solvent was completely evaporated under reduced pressure. The residue was diluted in dichloromethane and water. The separated organic layer was over MgSO4And (5) drying. Complete evaporation of the solvent under reduced pressure gave compound 3 (95%).
1H NMR(400MHz,CDCl3)δ＝12.36(s,1H,OH),8.08(d,J＝9.1Hz,2H,Ar-H),7.00(d,J＝9.1Hz,2H,Ar-H),6.21(s,1H,Ar-H),3.85(d,J＝14.6Hz,6H,2CH3O),2.83(t,J＝6.8Hz,2H,CH2-CH2-C(CH3)2),1.84(t,J＝6.8Hz,2H,CH2-CH2-C(CH3)2),1.34(s,6H,(CH3)2).13C NMR(101MHz,CDCl3)δ＝178.7(C＝O),161.5(C＝C),160.0(C＝C),159.4(C＝C),155.1(C＝C),153.7(C＝C),139.0(C＝C),129.9(2C,C＝C),123.2(C＝C),114.1(2C,C＝C),105.7(C＝C),99.9(C＝C),99.5(C＝C),75.9(C(CH3)2),60.1(CH3O),55.4(CH3O),31.7(CH2-CH2-C(CH3)2),26.6(2C,C(CH3)2),16.3(CH2-CH2-C(CH3)2).
3Example 3 preparation of compounds 4a-j (R ═ CH):
(1) compound 4a (R ═ CH)3) Preparation of
Figure BDA0002674137810000031
Compound 3(50mg, 0.136mmol) and K2CO3(38 mg, 2equ in acetone (2 ml)) stirred at room temperatureStirring for 10 minutes. Methyl iodide (2equ.) was added dropwise to the suspension over 10 minutes. The reaction was heated to reflux for 6 hours. After cooling to room temperature, the solvent was completely evaporated under reduced pressure. The residue was diluted in dichloromethane and water. The separated organic layer was over MgSO4And (5) drying. Complete evaporation of the solvent under reduced pressure gave compound 4a (85%).1H NMR(400MHz,CDCl3)δ＝8.06(d,J＝9.0Hz,2H,Ar-H),6.97(d,J＝9.0Hz,2H,Ar-H),6.22(s,1H,Ar-H),3.88(s,3H,OCH3),3.84(s,3H,OCH3),3.83(s,3H,OCH3),2.85(t,J＝6.7Hz,2H,CH2-CH2-C(CH3)2),1.85(t,J＝6.8Hz,2H,CH2-CH2-C(CH3)2),1.35(s,6H,(CH3)2).13C NMR(101MHz,CDCl3)δ＝174.3(C＝O),161.0(C＝C),159.0(C＝C),158.2(C＝C),155.7(C＝C),151.9(C＝C),141.0(C＝C),129.6(2C,C＝C),123.6(C＝C),113.9(2C,C＝C),108.8(C＝C),101.0(C＝C),96.5(C＝C),75.9(C(CH3)2),59.8(CH3O),56.2(CH3O),55.3(CH3O),31.9(CH2-CH2-C(CH3)2),26.6(2C,C(CH3)2),16.6(CH2-CH2-C(CH3)2).HRMS(TOF):calculated for C23H24O6:396.43,Found:397.18[M+1].
(2) Compound 4b (R ═ C)2H5) Preparation of
Figure BDA0002674137810000041
Compound 3(50mg, 0.136mmol) and K2CO3(38 mg, 2equ. placed in acetone (2 ml)) was stirred at room temperature for 10 minutes. Bromoethane (2equ.) was added dropwise to the suspension over 10 minutes. The reaction was heated to reflux for 6 hours. After cooling to room temperature, the solvent was completely evaporated under reduced pressure. The residue was diluted in dichloromethane and water. The separated organic layer was over MgSO4And (5) drying. Complete evaporation of the solvent under reduced pressure gave compound 4b (60%) as a white solidMelting point M.p.165.6-168.7 deg.Cf＝0.19(PE:EA＝3:1).1H NMR(400MHz,CDCl3)δ＝8.07(d,J＝8.9Hz,2H,Ar-H),6.98(d,J＝8.9Hz,2H,Ar-H),6.21(s,1H,Ar-H),4.09(q,J＝7.0Hz,2H,CH2CH3),3.85(s,3H,OCH3),3.84(s 3H,OCH3),2.85(t,J＝6.7Hz,2H,CH2-CH2-C(CH3)2),1.85(t,J＝6.8Hz,2H,CH2-CH2-C(CH3)2),1.51(t,J＝7.0Hz,3H,CH2CH3),1.35(s,6H,(CH3)2).13C NMR(101MHz,CDCl3)δ＝174.3(C＝O),160.9(C＝C),158.3(C＝C),158.1(C＝C),155.7(C＝C),151.9(C＝C),141.0(C＝C),129.6(2C,C＝C),123.7(C＝C),113.9(2C,C＝C),109.0(C＝C),100.9(C＝C),97.5(C＝C),75.8(C(CH3)2),64.8(OCH2),59.9(CH3O),55.4(CH3O),31.9(CH2-CH2-C(CH3)2),26.6(2C,C(CH3)2),16.6(CH2-CH2-C(CH3)2),14.6(CH2CH3).HRMS(TOF):calculated for C24H26O6:410.46,Found:411.20[M+1].
(3) Compound 4c (R ═ nC)3H7) Preparation of
Figure BDA0002674137810000042
Compound 3(50mg, 0.136mmol) and K2CO3(38 mg, 2equ. placed in acetone (2 ml)) was stirred at room temperature for 10 minutes. To the suspension was added dropwise n-bromopropane (2equ.) over 10 minutes. The reaction was heated to reflux for 6 hours. After cooling to room temperature, the solvent was completely evaporated under reduced pressure. The residue was diluted in dichloromethane and water. The separated organic layer was over MgSO4And (5) drying. Complete evaporation of the solvent under reduced pressure gave compound 4c (64%) as a white solid, m.p. 168.4-171.3 ℃. Rf＝0.38(PE:EA＝3:1).1H NMR(400MHz,CDCl3)δ＝8.07(d,J＝9.0Hz,2H,Ar-H),6.98(d,J＝9.0Hz,2H,Ar-H),6.22(s,1H,Ar-H),3.97(t,J＝6.7Hz,2H,OCH2),3.86(s,3H,OCH3),3.83(s,3H,OCH3),2.85(t,J＝6.8Hz,2H,CH2-CH2-C(CH3)2),1.92(q,J＝7.1Hz,2H,CH2CH3),1.85(t,J＝6.8Hz,2H,CH2-CH2-C(CH3)2),1.35(s,3H,CH3),1.34(s,3H,CH3),1.07(t,J＝7.4Hz,3H,CH2CH3).13C NMR(101MHz,CDCl3)δ＝174.2(C＝O),160.9(C＝C),158.5(C＝C),158.1(C＝C),155.7(C＝C),151.9(C＝C),141.0(C＝C),129.6(2C,C＝C),123.7(C＝C),113.9(2C,C＝C),109.0(C＝C),100.8(C＝C),97.5(C＝C),75.8(C(CH3)2),70.7(OCH2),59.9(CH3O),55.3(CH3O),31.9(CH2-CH2-C(CH3)2),26.6(2C,C(CH3)2),22.3(CH2CH3),16.6(CH2-CH2-C(CH3)2),10.5(CH2CH3).HRMS(TOF):calculated for C25H28O6:424.49,Found:425.21[M+1].
(4) Compound 4d (R ═ nC)5H11) Preparation of
Figure BDA0002674137810000051
Compound 3(50mg, 0.136mmol) and K2CO3(38 mg, 2equ. placed in acetone (2 ml)) was stirred at room temperature for 10 minutes. N-bromopentane (2equ.) was added dropwise to the suspension over 10 minutes. The reaction was heated to reflux for 6 hours. After cooling to room temperature, the solvent was completely evaporated under reduced pressure. The residue was diluted in dichloromethane and water. The separated organic layer was over MgSO4And (5) drying. The solvent was evaporated completely under reduced pressure to give compound 4d (67%) as a white solid with melting point M.p.137.2-140.2 ℃ Rf＝0.47(PE:EA＝3:1).1H NMR(400MHz,CDCl3)δ＝8.03(d,J＝7.4Hz,2H,Ar-H),6.95(d,J＝6.7Hz,2H,Ar-H),6.18(s,1H,Ar-H),3.96(t,J＝4Hz,2H,OCH2),3.82(s,3H,OCH3),3.79(s,3H,OCH3),2.83(t,J＝6.8Hz,2H,CH2-CH2-C(CH3)2),1.89(t,J＝6.7Hz,2H,OCH2CH2),1.83(d,J＝6.6Hz,2H,CH2-CH2-C(CH3)2),1.47–1.42(m,2H,CH2CH3),1.32(s,6H,(CH3)2),1.15-1.24(m,2H,CH2CH2CH3),0.86(t,J＝6.8Hz,3H,CH2CH3).13C NMR(101MHz,CDCl3)δ＝174.2(C＝O),160.9(C＝C),158.5(C＝C),158.1(C＝C),155.7(C＝C),151.9(C＝C),141.0(C＝C),129.6(2C,C＝C),123.7(C＝C),113.9(2C,C＝C),109.0(C＝C),100.8(C＝C),97.4(C＝C),75.8(C(CH3)2),69.3(OCH2),59.9(CH3O),55.3(CH3O),31.9(CH2-CH2-C(CH3)2),28.6(OCH2CH2),28.0(OCH2CH2CH2),26.6(2C,C(CH3)2),22.4,16.6(CH2-CH2-C(CH3)2),14.0(CH2CH3).HRMS(TOF):calculated for C27H32O6:452.54,Found:453.25[M+1].
(5) Compound 4e (R ═ CH)2CH2Br) preparation
Figure BDA0002674137810000052
Compound 3(50mg, 0.136mmol) and K2CO3(38 mg, 2equ. placed in acetone (2 ml)) was stirred at room temperature for 10 minutes. 1, 2-dibromoethane (2equ.) was added dropwise to the suspension over 10 minutes. The reaction was heated to reflux for 6 hours. After cooling to room temperature, the solvent was completely evaporated under reduced pressure. The residue was diluted in dichloromethane and water. The separated organic layer was over MgSO4And (5) drying. Complete evaporation of the solvent under reduced pressure gave compound 4e (44%) as a pale yellow solid, m.p.143.5-148.7 ℃ C. Rf＝0.28(PE:EA＝3:1).1H NMR(400MHz,CDCl3)δ＝8.06(d,J＝7.9Hz,2H,Ar-H),6.98(d,J＝7.8Hz,2H,Ar-H),6.26(s,1H,Ar-H),4.31(t,J＝6.7Hz,2H,OCH2),3.85(s,3H,OCH3),3.82(s,3H,OCH3),3.68(d,J＝7.5Hz,2H,CH2Br),2.86(t,J＝6.0Hz,2H,CH2-CH2-C(CH3)2),1.85(t,J＝6.6Hz,2H,CH2-CH2-C(CH3)2),1.35(s,6H,(CH3)2).13C NMR(101MHz,CDCl3)δ＝174.0(C＝O),161.1(C＝C),158.1(C＝C),157.1(C＝C),153.5(C＝C),152.3(C＝C),140.9(C＝C),129.6(2C,C＝C),123.5(C＝C),114.0(2C,C＝C),109.4(C＝C),102.5(C＝C),99.5(C＝C),76.0(C(CH3)2),69.5(OCH2),59.9(CH3O),55.3(CH3O),31.8(CH2-CH2-C(CH3)2),28.3(CH2Br),26.6(2C,C(CH3)2),16.7(CH2-CH2-C(CH3)2).HRMS(TOF):calculated for C24H25BrO6:490.08,Found:491.09[M+1].
(6) Compound 4f (R ═ CH)2CH2CH2Br) preparation
Figure BDA0002674137810000061
Compound 3(50mg, 0.136mmol) and K2CO3(38 mg, 2equ. placed in acetone (2 ml)) was stirred at room temperature for 10 minutes. 1, 2-dibromopropane (2equ.) was added dropwise to the suspension over 10 minutes. The reaction was heated to reflux for 6 hours. After cooling to room temperature, the solvent was completely evaporated under reduced pressure. The residue was diluted in dichloromethane and water. The separated organic layer was over MgSO4And (5) drying. Complete evaporation of the solvent under reduced pressure gave compound 4f (53%) as a pale yellow solid, m.p.180.2-185.5 ℃ C. Rf＝0.31(PE:EA＝3:1).1H NMR(400MHz,CDCl3)δ＝8.06(d,J＝8.9Hz,2H,Ar-H),6.99(d,J＝8.9Hz,2H,Ar-H),6.24(s,1H,Ar-H),4.14(t,J＝5.6Hz,2H,OCH2),3.86(s,3H,OCH3),3.80(s,3H,OCH3),3.69(d,J＝7.0Hz,2H,CH2Br),2.86(t,J＝6.7Hz,2H,CH2-CH2-C(CH3)2),2.40(p,J＝5.9Hz,2H,CH2CH2Br),1.86(t,J＝6.7Hz,2H,CH2-CH2-C(CH3)2),1.36(s,6H,(CH3)2).13C NMR(101MHz,CDCl3)δ＝174.2(C＝O),161.0(C＝C),158.1(2C,C＝C),155.6(C＝C),152.2(C＝C),151.2(C＝C),141.0(C＝C),129.6(2C,C＝C),123.6(C＝C),113.9(2C,C＝C),101.3(C＝C),97.7(C＝C),75.9(C(CH3)2),66.3(OCH2),59.8(CH3O),55.3(CH3O),32.0(CH2-CH2-C(CH3)2),30.9(CH2CH2Br),29.6(CH2Br),26.6(2C,C(CH3)2),16.6(CH2-CH2-C(CH3)2).HRMS(TOF):calculated for C25H27BrO6:504.38,Found:505.25[M+1].
(7) Compound 4g (R ═ CH)2CH2CH2CH2Br) preparation
Figure BDA0002674137810000062
Compound 3(50mg, 0.136mmol) and K2CO3(38 mg, 2equ. placed in acetone (2 ml)) was stirred at room temperature for 10 minutes. 1, 2-dibromobutane (2equ.) was added dropwise to the suspension over 10 minutes. The reaction was heated to reflux for 6 hours. After cooling to room temperature, the solvent was completely evaporated under reduced pressure. The residue was diluted in dichloromethane and water. The separated organic layer was over MgSO4And (5) drying. Complete evaporation of the solvent under reduced pressure gave 4g (78%) of the compound as a white solid with melting point M.p.139.4-142.6 ℃ Cf＝0.41(PE:EA＝3:1).1H NMR(400MHz,CDCl3)δ＝8.07(d,J＝8.9Hz,2H,Ar-H),6.99(d,J＝8.9Hz,2H,Ar-H),6.21(s,1H,Ar-H),4.04(t,J＝5.9Hz,2H,OCH2),3.86(s,3H,OCH3),3.81(s,3H,OCH3),3.53(t,J＝6.4Hz,2H,CH2Br),2.86(t,J＝6.7Hz,2H,CH2-CH2-C(CH3)2),2.22–2.15(m,2H,CH2CH2Br),2.09–2.02(m,2H,CH2CH2O),1.86(t,J＝6.7Hz,2H,CH2-CH2-C(CH3)2),1.36(s,6H,(CH3)2).13C NMR(101MHz,CDCl3)δ＝174.2(C＝O),160.1(C＝C),158.2(C＝C),158.1(C＝C),155.7(C＝C),152.1(C＝C),141.0(C＝C),129.6(2C,C＝C),123.6(C＝C),113.9(2C,C＝C),109.0(C＝C),101.1(C＝C),97.5(C＝C),75.9(C(CH3)2),67.9(OCH2),59.9(CH3O),55.4(CH3O),34.3(CH2Br),31.8(CH2-CH2-C(CH3)2),29.2(CH2CH2Br),27.4(CH2CH2O),26.6(2C,C(CH3)2),16.6(CH2-CH2-C(CH3)2).HRMS(TOF):calculated for C26H29BrO6:518.41,Found:519.12[M+1].
(8) Preparation of compound 4h (R ═ allyl)
Figure BDA0002674137810000071
Compound 3(50mg, 0.136mmol) and K2CO3(38 mg, 2equ. placed in acetone (2 ml)) was stirred at room temperature for 10 minutes. Allyl bromide (2equ.) was added dropwise to the suspension over 10 minutes. The reaction was heated to reflux for 6 hours. After cooling to room temperature, the solvent was completely evaporated under reduced pressure. The residue was diluted in dichloromethane and water. The separated organic layer was over MgSO4And (5) drying. Completely evaporating the solvent under reduced pressure to obtain a compound 4h (76%) as a white solid with a melting point of M.p.167.0-169.8 ℃ Rf＝0.25(PE:EA＝3:1).1H NMR(400MHz,CDCl3)δ＝8.07(d,J＝9.1Hz,2H,Ar-H),6.98(d,J＝9.1Hz,2H,Ar-H),6.22(s,1H,Ar-H),6.09(ddd,J＝21.9,10.5,4.7Hz,1H,CH2＝CH),5.67(dd,J＝17.3,1.6Hz,1H,CH2＝CH),5.31(dd,J＝10.6,1.6Hz,1H,CH2＝CH),4.60(d,J＝4.7Hz,2H,OCH2),3.86(s,3H,OCH3),3.83(s,3H,OCH3),2.86(t,J＝6.8Hz,2H,CH2-CH2-C(CH3)2),1.85(t,J＝6.8Hz,2H,CH2-CH2-C(CH3)2),1.35(s,6H,(CH3)2).13C NMR(101MHz,CDCl3)δ＝174.2(C＝O),161.0,158.2(C＝C),157.8(C＝C),155.7(C＝C),152.0(C＝C),141.9(C＝C),141.0(C＝C),132.4(C＝C),129.6(2C,C＝C),123.7(C＝C),117.6(C＝C),113.9(2C,C＝C),101.2(C＝C),98.0(C＝C),75.9(C(CH3)2),69.6(OCH2),59.9(CH3O),55.3(CH3O),31.9(CH2-CH2-C(CH3)2),26.6(2C,C(CH3)2),16.6(CH2-CH2-C(CH3)2).HRMS(TOF):calculated for C25H26O6:422.47,Found:423.20[M+1].
(9) Preparation of compound 4i (R ═ propargyl)
Figure BDA0002674137810000081
Compound 3(50mg, 0.136mmol) and K2CO3(38 mg, 2equ. placed in acetone (2 ml)) was stirred at room temperature for 10 minutes. Propargyl bromide (2equ.) was added dropwise to the suspension over 10 minutes. The reaction was heated to reflux for 6 hours. After cooling to room temperature, the solvent was completely evaporated under reduced pressure. The residue was diluted in dichloromethane and water. The separated organic layer was over MgSO4And (5) drying. Complete evaporation of the solvent under reduced pressure gave compound 4i (45%) as a white solid, m.p.155.7-161.5 ℃ C. Rf＝0.16(PE:EA＝3:1).1H NMR(400MHz,CDCl3)δ＝8.06(d,J＝8.9Hz,2H,Ar-H),6.98(d,J＝8.9Hz,2H,Ar-H),6.41(s,1H,Ar-H),4.80(s,2H,OCH2),3.85(s,3H,OCH3),3.83(s,3H,OCH3),2.87(t,J＝6.7Hz,2H,CH2-CH2-C(CH3)2),2.51(t,J＝2.4Hz,1H,CH),1.86(t,J＝6.7Hz,2H,CH2-CH2-C(CH3)2),1.36(s,6H,(CH3)2).13C NMR(101MHz,CDCl3)δ＝174.0(C＝O),161.0(C＝C),158.0(C＝C),156.5(C＝C),155.6(C＝C),152.1(C＝C),141.0(C＝C),129.6(2C,C＝C),123.5(C＝C),113.9(2C,C＝C),109.3(C＝C),102.3(C＝C),99.6(C＝C),78.2(HC≡C-),76.2(HC≡C-),76.0(C(CH3)2),59.8(CH3O),57.1(OCH2),55.4(CH3O),31.8(CH2-CH2-C(CH3)2),26.6(2C,C(CH3)2),16.7(CH2-CH2-C(CH3)2).HRMS(TOF):calculated for C25H24O6:420.45,Found:421.18[M+1].
(10) Preparation of compound 4j (R ═ benzyl)
Figure BDA0002674137810000082
Compound 3(50mg, 0.136mmol) and K2CO3(38 mg, 2equ. placed in acetone (2 ml)) was stirred at room temperature for 10 minutes. Benzyl bromide (2equ.) was added dropwise to the suspension over 10 minutes. The reaction was heated to reflux for 6 hours. After cooling to room temperature, the solvent was completely evaporated under reduced pressure. The residue was diluted in dichloromethane and water. The separated organic layer was over MgSO4And (5) drying. Complete evaporation of the solvent under reduced pressure gave compound 4j (63%) as a white solid, m.p.200.1-203.5 ℃ C. Rf＝0.34(PE:EA＝3:1).1H NMR(400MHz,CDCl3)δ＝8.08(d,J＝9.0Hz,2H,Ar-H),7.62(d,J＝7.4Hz,2H,Ar-H),7.37(t,J＝7.5Hz,2H,Ar-H),7.27(d,J＝7.1Hz,1H,Ar-H),6.99(d,J＝9.1Hz,2H,Ar-H),6.29(s,1H,Ar-H),5.18(s,2H,OCH2),3.86(s,3H,OCH3),3.84(s,3H,OCH3),2.86(t,J＝6.8Hz,2H,CH2-CH2-C(CH3)2),1.85(t,J＝6.7Hz,2H,CH2-CH2-C(CH3)2),1.35(s,3H,CH3),1.33(s,3H,CH3).13C NMR(101MHz,CDCl3)δ＝174.2(C＝O),161.0(C＝C),158.1(C＝C),157.7(C＝C),155.7(C＝C),152.1(C＝C),141.1(C＝C),136.7(C＝C),129.6(2C,C＝C),128.5(2C,C＝C),127.4(C＝C),126.5(2C,C＝C),123.6(C＝C),113.9(2C,C＝C),109.2(C＝C),101.4(C＝C),98.2(C＝C),75.9(C(CH3)2),70.5(OCH2),59.9(CH3O),55.4(CH3O),31.8(CH2-CH2-C(CH3)2),26.6(2C,C(CH3)2),16.6(CH2-CH2-C(CH3)2).HRMS(TOF):calculated for C29H28O6:472.53,Found:473.20[M+1].
Example 4 Activity test of novel 5-substituted Icaritin derivative 5
Cell line and solvent
Human hepatoma cell HEPG 2;
human colon cancer cells SW 480;
human lung cancer cell a 549;
human breast cancer cells MCF 7;
culturing the cells in RPMI 1640 containing 10% fetal bovine serum;
solvent: dimethylsulfoxide (abbreviated as DMSO).
Embodiment for detecting anti-tumor activity of cells by CCK-8 staining method
Selecting the cells with the ratio of the tumor living cells to be detected being more than 90 percent for experiment. Cell proliferation inhibition assay Using EnoGeneCellTMCounting Kit-8 (CCK-8 for short) cell viability detection Kit. The cells were digested, counted, and made into cell suspensions at a concentration of 1X 105/mL, and 100. mu.L of cell suspension (1X 104 cells per well) was added to each well of a 96-well plate; culturing the 96-well plate in a 5% CO2 incubator at 37 ℃ for 24 hours; adding 100 μ L of corresponding culture medium containing medicine into each well with an action concentration of 50 μ Mol/L (micromole/liter), and simultaneously setting up a negative control group, a solvent control group, and a positive control group (the positive controls are icaritin and camptothecin respectively), wherein each group has 5 wells; culturing the 96-well plate in a 5% CO2 incubator at 37 ℃ for 72 hours; adding 10. mu.L of CCK-8 solution into each well, and culturing the culture plateIncubating in the incubator for 4 hours, measuring the light absorption value (OD value for short) at 450nm by using an enzyme-labeling instrument, and calculating the inhibition rate of each compound on human liver cancer cell HEPG2, human colon cancer cell SW480, human lung cancer cell A549 and human breast cancer cell MCF 7.
The results are detailed in tables 1-3.
TABLE 1 tumor suppression Rate (%)
Figure BDA0002674137810000091
Figure BDA0002674137810000101
The experimental results in table 1 show that the 5-substituted icaritin derivative 4 of the invention has good in vitro anti-tumor activity, and the in vitro inhibition rate of 50 mu Mol/L action concentration on human liver cancer cell HEPG2, human colon cancer cell SW480, human lung cancer cell A549 and human breast cancer cell MCF7 is as high as 57-72%, which is equivalent to the inhibition activity of positive control drugs icaritin and camptothecin; can be used as a novel epimedium flavonoid candidate drug for antitumor clinical application.

Claims (3)

  1. The 1.5-substituted icaritin derivative has a structural formula shown in formula 4,
    Figure DEST_PATH_IMAGE001
    wherein R is selected from-C2H5，-nC3H7，-nC5H11，-CH2CH2Br，-CH2CH2CH2Br，-CH2CH2CH2CH2Br, allyl, -propargyl, -benzyl.
  2. 2. The method for synthesizing 5-substituted icaritin derivative 4 according to claim 1, comprising: 1) Icaritin 1 and formic acid react in a proper organic solvent to obtain a compound 2, 2), the compound 2 reacts with dimethyl sulfate in acetone in the presence of a base catalyst to obtain a compound 3, 3), and the compound 3 reacts with RX to obtain the 5-substituted icaritin derivative shown in the formula 4, wherein the synthetic route is shown as follows:
    Figure 509030DEST_PATH_IMAGE002
    ；
    wherein R is selected from-C2H5，-nC3H7，-nC5H11，-CH2CH2Br，-CH2CH2CH2Br，-CH2CH2CH2CH2Br, allyl, -propargyl, -benzyl.
  3. 3. The use of the 5-substituted icaritin derivative 4 according to claim 1 in the preparation of anti-liver cancer and anti-colon cancer drugs.
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