Cycloicariin dihydroflavonoid 3-gem-diol derivatives with anti-tumor activity and preparation method thereof

Abstract

The present application discloses a cycloicariin dihydroflavonoid 3-geminal diol derivative with anti-tumor activity in the field of medicinal chemistry, the structural formula of which is as follows: #imgabs0# wherein: R is selected from C 4‑7 The present invention provides a saturated hydrocarbon group, an unsaturated hydrocarbon group, an alicyclic group, and a benzyl group. Experiments have shown that the cycloicariin dihydroflavonoid 3-gem-diol derivatives (3) of the present invention have strong inhibitory activity against lung cancer and liver cancer, and their activity is stronger than that of their parent icariin.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and in particular to cycloicariin dihydroflavonoid 3-geminal diol derivatives with anti-tumor activity and a preparation method thereof. Background Art

[0002] The development of new anti-tumor drugs is of vital importance. As scientific research on traditional Chinese herbal medicine continues to deepen, more and more researchers have begun to pay attention to the anti-tumor efficacy of Chinese herbal medicine. Research results show that many natural medicines can kill tumor cells at multiple targets and have the advantages of relatively low cost and low toxicity. Epimedium is a traditional Chinese medicine belonging to the genus Epimedium of the Berberidaceae family. It is pungent, sweet, and warm in nature. Its dried leaves are used as medicine to treat impotence and spermatorrhea, kidney yang deficiency, rheumatic pain, muscle and bone weakness, numbness and cramps, etc. Pharmaceutical studies have shown that the main active ingredients of epimedium extracts include icariin, icariin, epimedium flavonoid derivatives, alkaloids, anthraquinones, lignans, phytosterols, anthocyanins, terpenoids, chlorogenic acid and other bioactive ingredients and nutrients such as essential fatty acids and trace elements. Modern pharmacological research has shown that Epimedium and its active ingredients not only have the functions of dilating coronary arteries, inhibiting microorganisms, anti-aging, and promoting bone cell growth, but also have multiple biological activities such as inhibiting tumors. Icaritin (1) is an active ingredient present in Epimedium medicinal materials. It is a flavonoid substance and is a yellow solid at room temperature. Its chemical name is 3,5,7-trihydroxy-2-(4-methoxyphenyl)-8-(3-methylbut-2-enyl)-4H-chromen-4-one, and its molecular formula is C 21 H 20 O6, with a molecular weight of 368.3799. Icaritin can also be produced by hydrolysis of icariin, the main active ingredient of epimedium. Icaritin is already available in my country for the treatment of advanced liver cancer. Cycloicariin (2) can be synthesized from icariin (1). The structures of icariin and cycloicariin are shown below.

[0003]

[0004] Studies have shown that icariin possesses a wide range of biological activities, including anti-tumor, anti-hepatic fibrosis, anti-osteoporosis, prostate function improvement, neuroprotection, immunosuppression, anti-inflammatory, and antioxidant properties. Like many natural products, icariin has several limitations, attracting pharmaceutical researchers to conduct in-depth research on its structure modification and activity.

[0005] Copper(II) chloride can be used as a chlorination agent, oxidation agent, and Lewis acid reagent in organic synthesis. In particular, copper chloride is an effective chlorination agent for various functional group compounds, and can achieve α-chlorination of carbonyl compounds and chlorination of aromatic compounds. For example, using carbon tetrachloride as the reaction solvent, copper(II) chloride reacts with phenol or alkoxybenzene compounds to produce ortho- or para-chlorinated products of the benzene ring.

[0006] Considering the chlorinating effect of copper chloride, the inventors hoped to use CuCl2 to introduce a halogen atom into the benzene ring of cycloicariin (2). However, unexpectedly, the reaction of cycloicariin (2) with copper (II) chloride dihydrate (CuCl2·2H2O) in an alcohol solvent did not form the corresponding chloride, but instead unexpectedly obtained a cycloicariin dihydroflavonoid 3-gem-diol derivative (3) with a completely new structure. Activity studies confirmed that compound 3 has strong inhibitory activity against lung cancer and liver cancer. Summary of the Invention

[0007] In view of the deficiencies of the prior art, the present invention transforms the structure of icariin and provides a cycloicariin dihydroflavonoid 3-gem-diol derivative with anti-tumor activity.

[0008] One of the purposes of the present invention is to provide a cycloicariin dihydroflavonoid 3-geminal diol derivative (3) having anti-tumor activity, the structural formula of which is shown below:

[0009]

[0010] Where: R is selected from C 4-7 Saturated hydrocarbon group, unsaturated hydrocarbon group and alicyclic group, benzyl group.

[0011] A second object of the present invention is to provide a method for preparing cycloicariin dihydroflavonoid 3-geminal diol derivatives, comprising the following steps:

[0012] Step 1: Icaritin (1) is heated in formic acid for reflux reaction to obtain cycloicariin (2).

[0013] Step 2: Cycloicariin (2) is reacted with alcohol in the presence of a specific catalyst under specific conditions to obtain cycloicariin dihydroflavonoid 3-geminal diol derivatives (3); wherein: R is selected from C 4-7 Saturated hydrocarbon group, unsaturated hydrocarbon group and alicyclic group, benzyl group; the reaction route is as follows:

[0014]

[0015] Preferably, the catalyst in step 2 is selected from CuCl2, CuBr2, CuI and their corresponding hydrates.

[0016] The specific conditions of step 2 refer to: reacting at 10-100°C without a solvent, or reacting at 10-200°C with acetonitrile, dichloromethane, chloroform, tetrahydrofuran, DMF or DMSO as a solvent.

[0017] For further optimization, the solvent is preferably dichloromethane.

[0018] Preferably, the reaction temperature is 20-60°C.

[0019] Preferably, the catalyst is selected from CuCl2.2H2O or CuBr2.

[0020] Preferably, the alcohol in step 2 is an alcohol having a substituent corresponding to R, specifically C 4-7 Saturated alcohol, C 4-7 Unsaturated alcohol, C 4-7 Alicyclic alcohol or benzyl alcohol.

[0021] The results of the activity test showed that cycloicariin dihydroflavonoid 3-gem-diol derivatives (3) could significantly inhibit the growth of two tumor cells - lung cancer A549 and liver cancer SMMC-7721, and its activity was stronger than that of its parent structure icariin and cycloicariin.

[0022] The third object of the present invention is to provide the use of cycloicariin dihydroflavonoid 3-geminal diol derivatives (3) in the preparation of anti-tumor drugs.

[0023] Specifically, the anti-tumor drug is a drug for liver cancer or lung cancer. DETAILED DESCRIPTION

[0024] The present invention will be further illustrated by specific examples below, but these examples are not intended to limit the scope of protection of the present invention. Without departing from the scope of the present invention, those skilled in the art may make improvements to the preparation method and the apparatus used, and such improvements should also be considered within the scope of protection of the present invention. Therefore, the scope of protection of the patent for this invention shall be based on the appended claims.

[0025] In the following examples, unless otherwise stated, the experimental methods are generally carried out according to conventional conditions or conditions recommended by the manufacturer; the raw materials and reagents shown can be obtained through commercial purchase.

[0026] Example A: Preparation of cycloicariin (2)

[0027]

[0028] Weigh icariin (50 mg, 0.136 mmol) into a round-bottom flask, add 4 mL of formic acid, and place the reaction flask in an 85°C oil bath for reflux reaction. At this time, the reaction solution becomes clear. Continue the reaction, and a yellow solid gradually precipitates from the reaction solution. React for 4 hours, and use thin-layer chromatography with a volume ratio of 4:1 petroleum ether-ethyl acetate as a developing agent. The reaction endpoint is determined when no reactant icariin is detected on the thin-layer chromatography plate. After the reaction is completed, place the reaction flask in a 4°C refrigerator for 10 minutes, filter, and dry to obtain a yellow powdery solid cycloicariin (2, 45 mg, 89.7%). The product is a light yellow solid; R f =0.23 (eluent: petroleum ether: ethyl acetate = 6:1). 1 H NMR(300MHz,Chloroform-d)δ11.47(s,1H),8.15(d,J=8.6Hz,2H),7.01(d,J=8.7Hz,2H),6.7 0(s,1H),6.23(s,1H),3.87(s,3H),2.87(t,J=6.8Hz,2H),1.87(t,J=6.8Hz,2H),1.37(s,6H). 13 C NMR (101 MHz, Chloroform-d) δ177.62, 161.25, 160.24, 158.54, 155.17, 153.26, 136.46, 129.88, 123.20, 114.28, 104.82, 103.71, 99.09, 75.19, 55.32, 28.16, 26.78, 26.71. The compound was identified as cycloicariin by comparison of the NMR data with the literature.

[0029] Example B: Preparation of cycloicariin dihydroflavonoid 3-gem-diol derivatives (3)

[0030] Cycloicariin (2,50 mg, 0.136 mmol), CuCl2·2H2O (115 mg, 0.675 mmol), and ROH alcohol (2-4 mL, excess) were weighed into a reaction flask and stirred at room temperature for 3 h. The reaction mixture was extracted twice with ethyl acetate and water. The organic layer was separated and dried over MgSO4. The residue was concentrated in vacuo and chromatographed using a 3:1 ratio of petroleum ether to ethyl acetate to afford the desired product, cycloicariin dihydroflavonoid 3-gem-diol derivative (3,50.6 mg, 90%), as a yellow powdery solid.

[0031]

[0032] Table 1 Synthesis yield of cycloicariin dihydroflavonoid 3-gem-diol derivatives (3)

[0033]

[0034] To a dry round-bottom flask, cycloicariin (2, 50 mg, 0.135 mmol), CuCl2·2H2O (115 mg, 0.675 mmol), and 3 mL of n-butanol were added and reacted at 50°C for 3 h. Ethyl acetate and water were added to the reaction mixture for extraction and separation. The resulting organic layer was washed twice with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography (eluent: petroleum ether:ethyl acetate = 3:1) to obtain the desired product 3a as a light yellow solid (49.5 mg, 80% yield). Mp 114-116°C, R f =0.27(PE:EA=3:1), 1 H NMR (300MHz, CDCl3) δ11.37 (s, 1H), 7.74–7.43 (m, 2H), 6.97 (ddd, J = 16.9, 8.8, 3.0Hz, 2H), 6.07 (dd, J=10.8,3.0Hz,1H),3.84(dd,J=8.7,2.9Hz,3H),3.44(td,J=6.5,2.9Hz,1H),3.36–3.14(m,1H),2.8 0(ddt,J=14.4,10.4,7.3Hz,1H),2.74–2.48(m,2H),1.46(dq,J=11.7,4.7,2.9Hz,2H),1.41–1.28(m ,7H),1.22(dtq,J=11.8,7.2,4.4,3.6Hz,2H),1.08(dtq,J=11.5,7.7,4.4Hz,1H),0.82–0.68(m,3H). 13 C NMR (101MHz, CDCl3) δ191.21,187.33,178.67,165.70,164.13,163.16,161.27,160.69,156.0 6,155.38,129.89,128.93,124.95,124.50,113.91,113.65,105.92,105.88,104.95,102.67, 101.97,99.51,99.18,98.34,89.84,76.44,64.09,63.44,55.32,31.78,31.69,31.36,31.31, 27.08,26.80,26.78,26.41,19.07,19.02,16.23,16.19,13.63,13.59.HRMS-ESI(m / z):calcd for C 25 H 30 O8Na[M+Na]+ :481.1833,found481.1830.

[0035]

[0036] To a dry round-bottom flask, cycloicariin (2, 50 mg, 0.135 mmol), CuCl2·2H2O (115 mg, 0.675 mmol), and 3 mL of isobutanol were added and reacted at 50°C for 3 h. Ethyl acetate and water were added to the reaction mixture for extraction and separation. The resulting organic layer was washed twice with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography (eluent: petroleum ether:ethyl acetate = 3:1) to afford the desired product 3b as a light yellow solid (39.1 mg, 63% yield). Mp: 163-165°C, R f =0.31(PE:EA=3:1), 1 H NMR (300MHz, CDCl3) δ11.38–10.53(m,1H),7.74–7.43(m,2H),6.97(dd,J=14.3,8.9Hz,2H),6.06(d,J=13.3Hz,1H),4.82(s,1H),3.84(d,J=7 .3Hz,3H),3.23–2.86(m,2H),2.86–2.62(m,2H),1.89–1.73(m,2H),1. 62(ddd,J=10.3,8.1,5.1Hz,1H),1.48–1.32(m,6H),0.78–0.56(m,6H). 13 C NMR (101MHz, CDCl3) δ191.30,187.29,178.82,165.67,164.13,163.17,161.29,160.69,15 6.02,155.39,129.96,129.00,124.84,124.41,113.89,113.65,105.90,105.73,104.71,1 02.76,102.06,99.57,98.41,98.34,89.90,76.44,70.63,70.08,55.36,55.30,31.78,31. 70,28.22,28.06,27.03,26.78,26.42,19.18,19.13,19.07,16.22.HRMS-ESI(m / z):calcd forC 25 H 30 O8Na[M+Na] + :481.1833,found 481.1827.

[0037]

[0038] To a dry round-bottom flask, cycloicariin (2,50 mg, 0.135 mmol), CuCl2·2H2O (115 mg, 0.675 mmol), and 3 mL of n-pentanol were added and reacted at 50°C for 6 h. Ethyl acetate and water were added to the reaction mixture for extraction and separation. The resulting organic layer was washed twice with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography (eluent: petroleum ether:ethyl acetate = 3:1) to afford the desired product 3c as a light yellow solid (43 mg, 67% yield). Mp: 139-141°C, R f =0.3(PE:EA=3:1), 1 H NMR (300MHz, CDCl3) δ10.98(d,J=306.4Hz,1H),7.58(dd,J=111.9,8.6Hz,2H),6.97(dd,J=16.7,8. 6Hz,2H),6.07(d,J=11.1Hz,1H),3.84(d,J=8.7Hz,3H),3.46–3.40(m,1H),3.25(ddt,J=71.9,9.5, 6.6Hz,1H),2.85–2.56(m,3H),1.91–1.72(m,2H),1.46(q,J=6.6Hz,1H),1.37(dd,J=12.6,4.2Hz,7 H),1.24(s,1H),1.15(qq,J=8.3,4.4,2.7Hz,2H),1.10–0.97(m,2H),0.76(dt,J=23.8,6.9Hz,3H). 13 C NMR (101MHz, CDCl3) δ191.16,187.33,165.70,164.18,163.20,161.33,160.72,155.39,12 9.93,128.96,124.94,124.50,113.91,113.67,105.92,104.93,102.68,101.99,99.53,99. 24,99.14,98.42,98.33,89.83,76.43,64.36,63.72,55.38,55.29,31.78,31.70,29.70,29 .00,28.94,28.03,27.13,26.76,26.41,22.21,22.16,16.19,13.94.HRMS-ESI(m / z):calcd for C 26 H 32 O8Na[M+Na]+ :495.1989,found 495.1985.

[0039]

[0040] To a dry round-bottom flask, cycloicariin (2, 50 mg, 0.135 mmol), CuCl2·2H2O (115 mg, 0.675 mmol), and 3 mL of isoamyl alcohol were added and reacted at 50°C for 6 h. Ethyl acetate and water were added to the reaction mixture for extraction and separation. The resulting organic layer was washed twice with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography (eluent: petroleum ether:ethyl acetate = 3:1) to afford the desired product 3d as a light yellow solid (35.2 mg, 55% yield). Mp 106-108°C, R f =0.29(PE:EA=3:1), 1 H NMR (300MHz, CDCl3) δ10.59(s,1H),7.72(d,J=8.5Hz,1H),7.44(d,J=8.7Hz,1H),6.99(d,J=8.5Hz,1H),6.9 7–6.93(m,1H),6.07(d,J=10.8Hz,1H),4.80(s,1H),3.88–3.80(m,3H),3.46(td,J=6.7,2.4Hz,1H),3.35(d d,J=9.7,6.4Hz,1H),3.20(dd,J=9.6,7.0Hz,1H),2.84–2.74(m,1H),2.73–2.57(m,2H),1.90–1.73(m,2H), 1.56(dp,J=13.1,6.5Hz,1H), 1.37(dd,J=13.0,7.2Hz,6H), 1.23(dd,J=9.8,5.1Hz,1H), 0.78–0.60(m,6H). 13C NMR (101MHz, CDCl3) δ191.26,187.36,178.70,165.71,164.14,163.18,161.29,160.70,156.06 ,155.37,129.93,129.85,128.96,124.95,124.50,113.94,113.67,105.94,104.97,102.65,101 .95,99.51,99.27,99.16,98.43,98.32,89.86,76.44,62.66,62.00,55.38,55.27,38.05,31.7 8,31.70,27.04,26.79,26.47,24.66,22.57,22.41,22.19,21.93,16.23.HRMS-ESI(m / z):calcd forC 26 H 32 O8Na[M+Na] + :495.1989,found 495.1977.

[0041]

[0042] To a dry round-bottom flask, cycloicariin (2,50 mg, 0.135 mmol), CuCl2·2H2O (115 mg, 0.675 mmol), 3 mL of 3-butene-1-ol, and 2 mL of dichloromethane were added and allowed to react at room temperature for 4 h. Ethyl acetate and water were added to the reaction mixture for extraction and separation. The resulting organic layer was washed twice with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography (eluent: petroleum ether:ethyl acetate = 3:1) to afford the desired product 3e as a light yellow solid (40 mg, 65% yield). Mp: 156.5-157.5°C, R f =0.26(PE:EA=3:1), 1H NMR(300MHz, CDCl3)δ11.36(s,1H),7.75–7.69(m,1H),7.47–7.41(m,1H),7.01–6.93(m,2 H),6.07(d,J=10.7Hz,1H),5.61–5.41(m,1H),4.97–4.90(m,1H),4.86–4.81(m,1H),3.84( d,J=8.4Hz,3H),3.49(q,J=6.4Hz,1H),3.42–3.18(m,1H),2.83–2.73(m,1H),2.69–2.62( m,1H),2.23(q,J=6.8Hz,1H),2.09(q,J=6.8Hz,1H),1.90–1.75(m,2H),1.42–1.33(m,6H). 13 C NMR (101MHz, CDCl3) δ191.09,187.18,178.60,165.73,164.20,163.23,161.35,160.77,155.96, 155.32,134.29,134.09,129.92,128.97,124.80,124.32,116.95,116.57,113.95,113.70,105.9 5,105.94,104.91,102.74,102.05,99.57,99.27,99.23,98.44,98.40,89.78,63.77,63.26,55. 36,55.32,33.79,31.76,31.68,27.14,26.85,26.76,26.38,16.24,16.19.HRMS-ESI(m / z):calcd for C 25 H 28 O8Na[M+Na] + :479.1676,found 479.1665.

[0043]

[0044] To a dry round-bottom flask, cycloicariin (2, 50 mg, 0.135 mmol), CuCl2·2H2O (115 mg, 0.675 mmol), 3 mL of cyclopentanol, and 2 mL of dichloromethane were added and reacted at 50°C for 6 h. Ethyl acetate and water were added to the reaction mixture for extraction and separation. The resulting organic layer was washed twice with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (eluent: petroleum ether:ethyl acetate = 3:1) to obtain the desired product 3f as a light yellow solid (41 mg, 64% yield). f=0.37(PE:EA=3:1), 1 H NMR(300MHz, CDCl3)δ10.57(d,J=1.4Hz,1H),7.77–7.71(m,2H),7.48–7.41(m,1H),7.0 2–6.96(m,2H),6.96–6.92(m,1H),6.04(s,1H),4.80(s,1H),4.20–4.01(m,1H),3.85(s ,3H),3.83(d,J=6.3Hz,2H),2.82–2.71(m,2H),2.69(s,1H),2.66–2.59(m,1H),1.84(d d,J=11.6,5.2Hz,2H),1.81–1.76(m,1H),1.59–1.52(m,2H),1.36(s,3H),1.34(s,3H). 13 C NMR (101MHz, CDCl3) δ191.18,164.13,161.18,160.65,155.88,130.26,130.24,125.87,113.48,106.65,1 01.84,99.32,98.23,89.76,55.38,55.27,33.57,32.40,31.78,26.91,26.59,26.55,23.74,23.33,16.56.

[0045]

[0046] To a dry round-bottom flask, add cycloicariin (2, 50 mg, 0.135 mmol), CuCl2·2H2O (115 mg, 0.675 mmol), 1 mL of cyclohexanol, and 2 mL of dichloromethane. The mixture was reacted at 50°C for 6 h. Ethyl acetate and water were added to the reaction mixture for extraction and separation. The resulting organic layer was washed twice with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (eluent: petroleum ether:ethyl acetate = 3:1) to obtain the desired product as a light yellow solid (3 g, 32.2 mg, in a 49% yield). f =0.31(PE:EA=3:1), 1H NMR (300MHz, CDCl3) δ10.58(d,J=5.7Hz,1H),7.78(dd,J=16.6,8.5Hz,2H),6.95(dd,J=18.9,8.5Hz ,2H),6.03(s,1H),4.88(s,1H),3.87–3.81(m,3H),3.70–3.50(m,1H),2.79(dt,J=16.6,6.8Hz,1H), 2.69(d,J=6.6Hz,1H),2.58(dt,J=17.0,7.0Hz,1H),1.85(dt,J=13.7,6.7Hz,1H),1.77(q,J=6.9Hz, 1H), 1.39 (d, J=11.9Hz, 5H), 1.31 (s, 3H), 1.23 (d, J=11.0Hz, 2H), 1.00 (dq, J=18.5, 9.8, 9.2Hz, 4H). 13 C NMR (101MHz, CDCl3) δ191.22,164.10,161.22,160.66,130.27,125.83,113.42,113.30,101.81,9 9.31,89.93,73.52,55.38,55.24,33.50,33.00,31.81,26.87,26.81,26.47,25.24,24.12,16.57.

[0047]

[0048] To a dry round-bottom flask, add cycloicariin (2, 50 mg, 0.135 mmol), CuCl2·2H2O (115 mg, 0.675 mmol), 1 mL of benzyl alcohol, and 2 mL of dichloromethane. The mixture was reacted at 50°C for 6 h. Ethyl acetate and water were added to the reaction mixture for extraction and separation. The resulting organic layer was washed twice with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (eluent: petroleum ether:ethyl acetate = 3:1) to obtain the desired product 3h as a light yellow solid (40.1 mg, 60% yield). f =0.35(PE:EA=3:1), 1H NMR(300MHz, CDCl3)δ10.61(d,J=10.2Hz,1H),7.84–7.49(m,2H),7.18(dt,J=4.5, 2.3Hz,3H),7.07–6.94(m,4H),6.05(s,1H),4.44(s,1H),4.28(d,J=12.2Hz,1H),3 .86(d,J=4.2Hz,3H),2.71(ddd,J=16.7,8.2,6.2Hz,1H),2.47(dt,J=16.9,6.3Hz, 1H), 1.77 (dt, J=12.8, 6.1Hz, 1H), 1.67 (dd, J=8.2, 5.9Hz, 1H), 1.34–1.26 (m, 6H). 13 C NMR (101MHz, CDCl3) δ190.92,164.23,161.33,160.91,155.19,136.93,130.03,128.20,127.48,126.84, 124.68,113.80,106.30,102.10,99.52,98.57,98.45,89.79,65.83,55.43,31.65,27.29,26.25,16.08.

[0049] Example C: Tumor Growth Inhibitory Activity Test

[0050] Human lung cancer A549 and human liver cancer SMMC-7721 cells growing in logarithmic growth were added to a 96-well plate, with 100 μL per well containing approximately 3,000 cells. Compound (3) obtained in Example 1 above was then added, and icariin (1) and cycloicariin (2) were added as positive controls. Three parallel wells were set up in each group, and the cells were cultured at 37°C in a carbon dioxide incubator for 48 hours. Four hours before the end of the experiment, MTT (20 mg / mL) solution was added at 20 μL / well, and the cells were cultured for another 4 hours. The culture medium was discarded, and DMSO was added at 150 μL / well. After the crystals dissolved, the OD value of each well was measured at a wavelength of 490 nm on a microplate reader. The half-maximal inhibitory concentration (IC50) was then calculated using GraphPad Prism software. 50 value).

[0051] The results are shown in Table 2. Compared with the positive control icariin, the inhibition rate of compound (3a-1) was higher than that of icariin at a concentration of 50 μMol / L for 48 hours. The inhibition rates of all synthesized compounds on human lung cancer A549 and human liver cancer SMMC-7721 cells exceeded 90%. At the same time, the IC50 values ​​of the synthesized cycloicariin dihydroflavonoid 3-gem-diol derivatives on human lung cancer A549 and human liver cancer SMMC-7721 were 9.95 to 27.39 μMol / L and 12.39 to 31.47 μMol / L, respectively, indicating that these cycloicariin dihydroflavonoid 3-gem-diol derivatives (3) have excellent inhibitory activity against the growth of lung cancer and liver cancer.

[0052] Table 2. Inhibitory activity of compound 3 against lung cancer A549 and liver cancer SMMC-7721 a

[0053]

[0054] a: The test solvent was DMSO, b: The test drug concentration was 50 μMol / L, *: P < 0.01.

[0055] The above is only an embodiment of the present invention, and the common knowledge such as the specific structure and characteristics of the scheme is not described in detail here. It should be pointed out that for those skilled in the art, without departing from the structure of the present invention, several variations and improvements can be made, which should also be regarded as the scope of protection of the present invention, and these will not affect the effect of the implementation of the present invention and the practicality of the patent. The scope of protection required by this application shall be based on the content of its claims, and the specific implementation methods and other records in the specification can be used to interpret the content of the claims.

Claims

1. A cycloicariin dihydroflavonoid 3-geminal diol derivative having anti-tumor activity, characterized in that: The structural formula is shown below: Where: R is selected from C 4-7 Saturated hydrocarbon group, unsaturated hydrocarbon group and alicyclic group, benzyl group.

2. The method for preparing the cycloicariin dihydroflavonoid 3-geminal diol derivatives with anti-tumor activity according to claim 1, characterized in that: The following steps are involved: Step 1: Icaritin (1) is heated in formic acid for reflux reaction to obtain cycloicariin (2). Step 2: Cycloicariin (2) is reacted with alcohol in the presence of a specific catalyst under specific conditions to obtain cycloicariin dihydroflavonoid 3-geminal diol derivatives (3); wherein: R is selected from C 4-7 Saturated hydrocarbon group, unsaturated hydrocarbon group and alicyclic group, benzyl group; the reaction route is as follows:

3. The preparation method according to claim 2, wherein: The catalyst in step 2 is selected from CuCl2, CuBr2, CuI and their corresponding hydrates.

4. The preparation method according to claim 3, wherein: The specific conditions of step 2 refer to: reacting at 10-100°C without a solvent, or reacting at 10-200°C with acetonitrile, dichloromethane, chloroform, tetrahydrofuran, DMF or DMSO as a solvent.

5. The preparation method according to claim 4, characterized in that: The solvent is preferably dichloromethane.

6. The preparation method according to claim 5, characterized in that: The reaction conditions are 20-60°C.

7. The preparation method according to any one of claims 4 to 6, characterized in that: The catalyst is selected from CuCl2.2H2O or CuBr2.

8. The preparation method according to claim 7, characterized in that: The alcohol in step 2 is: C 4-7 Saturated alcohol, C 4-7 Unsaturated alcohol, C 4-7 Alicyclic alcohol or benzyl alcohol.

9. Use of the cycloicariin dihydroflavonoid 3-gem-diol derivatives with anti-tumor activity according to claim 1 in the preparation of anti-tumor drugs.

10. The use according to claim 9, characterized in that The anti-tumor drug is a drug for liver cancer or lung cancer.

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