A nitrogen oxide free radical derivative of rhamnosus and its synthesis method and application

Abstract

The present invention belongs to the technical field of organic chemical synthesis, and specifically relates to a nitrogen oxide free radical derivative of rhubarb and its synthesis method and application. The present invention takes rhubarb, a lipid-lowering medicinal substance of traditional Chinese medicine, as the research object, selects its 3rd hydroxyl group as the modification site, and based on different length carbon chain substitution, A 3 Based on the reaction mechanisms of coupling, esterification and pharmacophore splicing, six active intermediate nitroxide free radicals were introduced into the structure of emodin. 50 nitroxide free radical derivatives of emodin in three series and 8 other derivatives were designed and synthesized. Several synthetic methods for novel nitroxide free radical derivatives of emodin with mild reaction conditions, environmental friendliness and high yield were established. The novel nitroxide free radical derivatives of emodin provided have low toxicity to normal liver cells, significant anti-proliferative activity against liver cancer cells, and are novel active molecules with better effects than emodin, providing a new idea for the preparation of anti-tumor drugs.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemical synthesis, and particularly relates to a rhubarb nitrogen oxide free radical derivative and a synthesis method and application thereof. Background Art

[0002] Emodin is a trihydroxyanthraquinone compound extracted from the Polygonum cuspidatum plant of the Polygonaceae family. It is the active ingredient of the Chinese herbal medicine rhubarb. Studies have found that emodin not only has the effect of lowering blood lipids, but also has an inhibitory effect on cancer cells such as lung cancer and bladder cancer. Although emodin has an inhibitory effect on many cancer cells, its own anti-cancer activity is relatively low.

[0003] Hyperlipidemia is a major risk factor for liver cancer, and identifying anti-liver cancer compounds from lipid-lowering drugs has become a new strategy for research. Emodin, a lipid-lowering agent, has a promising lipid-lowering effect. Given its inhibitory effects on cancer cells, it appears to offer a promising new avenue for identifying anti-liver cancer compounds.

[0004] If emodin can be used as a research object and appropriately modified to obtain a substance with good anti-liver cancer activity, it will be of great significance to this field. Summary of the Invention

[0005] In order to solve the above technical problems, the present invention provides a nitrogen oxide free radical derivative of emodin and its synthesis method and application, by modifying the 3rd hydroxyl group of emodin, based on different length carbon chain substitution, A 3 Through coupling and esterification reaction mechanism, nitroxide free radicals were introduced into the structure of emodin, and a new emodin nitroxide free radical derivative with high yield and significant anti-hepatocancer activity was synthesized.

[0006] The technical solutions of the present invention are as follows:

[0007] In a first aspect of the present invention, a rhamnolide nitroxide free radical derivative is provided, wherein the structure of the rhamnolide nitroxide free radical derivative is selected from one of Formulas 1 to 3:

[0008]

[0009] The R group is a nitroxide free radical, and R1 and R2 are different active functional groups.

[0010] Preferably, when the rhamnosine nitroxide free radical derivative is of Formula 1 or Formula 3, the nitroxide free radical is selected from any one of Formulas 1 to 4:

[0011]

[0012] When the rhamnosine nitroxide free radical derivative is of the general formula 2, the nitroxide free radical is selected from any one of Formulas 5 to 6:

[0013]

[0014] Preferably, the emodin nitrogen oxide free radical derivative of formula 1 is prepared by the following method:

[0015] The hydroxyl group at position 3 of emodin was used as the modification site, and hydroxyalkyl side chains of different lengths were introduced at position 3 through a substitution reaction with bromohydrin. Then, the nitroxide radical containing a carboxyl group was connected to the side chain through an esterification reaction to synthesize emodin nitroxide radical derivatives with different carbon chain lengths, as shown in the general formula 1.

[0016] Preferably, the method is specifically:

[0017] Rhamnocarb and bromohydrin are used as raw materials, Cs2CO3 is used as a catalyst, and DMF (N,N-dimethylformamide) is used as a solvent. The mixture is heated to 50-70°C under the protection of Ar gas and reacted at a constant temperature for 8-10 hours. The solvent is then recovered by distillation under reduced pressure, dissolved with water, and the pH is adjusted to less than 7 with acid. The precipitate is filtered and washed with ethyl acetate to obtain an intermediate of a rhamnocarb derivative with carbon chain substitution of different lengths. The intermediate and a carboxyl-containing nitroxide free radical are then used as raw materials, EDCI (carbodiimide hydrochloride) and DMAP (4-dimethylaminopyridine) are used as catalysts, and DMF is used as a solvent. The mixture is reacted at room temperature under the protection of Ar gas. The reaction liquid is extracted with ethyl acetate, washed with water, dried, and separated by chromatography to finally obtain an rhamnocarb nitroxide free radical derivative of general formula 1.

[0018] Preferably, the bromoalcohol is selected from any one of 2-bromoethanol, 3-bromo-1-propanol, 4-bromo-1-butanol, 5-bromo-1-pentanol and 6-bromo-1-hexanol;

[0019] Preferably, the carboxyl-containing nitroxide radical is selected from any one of Formulas 1 to 4:

[0020]

[0021] The synthetic route of the emodin nitrogen oxide free radical derivative is as follows:

[0022]

[0023] Preferably, the rhamnosine nitrogen oxide free radical derivative of general formula 2 is prepared by the following method:

[0024] The hydroxyl group at position 3 of emodin was used as the modification site, and propynyl was introduced into its structure by bromopropynyl substitution, and then A 3In the coupling reaction, the synthesized nitroxide free radical containing terminal aldehyde and secondary amine are dehydrated and condensed under the action of a transition metal catalyst to generate the nitroxide free radical derivative of the rhamnolide propargylamine type of general formula 2.

[0025] Preferably, the method is specifically:

[0026] First, using emodin and propargyl bromide as raw materials, DMF as solvent, and anhydrous K2CO3 as catalyst, under the protection of Ar gas, heating to 60-80°C for reaction for 4 hours, TLC detection until the reaction is complete, extraction, washing, drying and column chromatography separation and purification are performed to obtain a propargyl-substituted emodin derivative; then, using a propargyl-substituted emodin derivative, an aldehyde-containing nitrogen oxide free radical and a secondary amine as raw materials, toluene as solvent, and CuBr as catalyst, respectively, under the protection of Ar gas, heating to 70-90°C for reaction for 7-9 hours, TLC detection until the reaction is complete, column chromatography separation and purification are performed to finally obtain an emodin nitrogen oxide free radical derivative of general formula 2.

[0027] Preferably, the aldehyde-containing nitroxide radical is selected from any one of Formula 5 to Formula 6:

[0028]

[0029] Preferably, the secondary amine is selected from any one of Formula 7 to Formula 19:

[0030]

[0031]

[0032] The synthetic route of the emodin nitrogen oxide free radical derivative is as follows:

[0033]

[0034] Preferably, the rhamnosine nitrogen oxide free radical derivative of general formula 3 is prepared by the following method:

[0035] Using the hydroxyl group at position 3 of emodin as the modification site, the synthesized carboxyl-containing nitroxide free radical was directly connected to the emodin structure through dehydration condensation to obtain the emodin nitroxide free radical derivative.

[0036] Preferably, the method is specifically:

[0037] Using emodin and carboxyl-containing nitroxide free radical as raw materials, DMF as solvent, EDCI and DMAP as catalysts, the reaction was carried out under Ar gas protection for 6 to 8 hours, and TLC tracking and monitoring was performed until the reaction was complete. After the reaction was terminated, the product was extracted, washed, dried, filtered, and separated and purified by silica gel column chromatography to finally obtain the emodin nitroxide free radical derivative of general formula 3;

[0038] Preferably, the carboxyl-containing nitroxide free radical is selected from any one of Formulas 1 to 4 above.

[0039] The synthetic route of the emodin nitrogen oxide free radical derivative is as follows:

[0040]

[0041] In the second aspect of the present invention, there is provided a use of the above-mentioned rhamnosin nitrogen oxide free radical derivative in anti-tumor drugs.

[0042] Preferably, the anti-tumor drug is an anti-liver cancer drug.

[0043] The beneficial effects of the present invention are:

[0044] (1) The present invention takes rhubarb as the lipid-lowering medicinal substance of traditional Chinese medicine, emodin, as the research object, selects its 3rd hydroxyl group as the modification site, and based on the substitution of different length carbon chains, A 3 By using the reaction mechanisms of coupling, esterification, and pharmacophore splicing, six active intermediate nitroxides were introduced into the structure of emodin. Fifty nitroxide derivatives of emodin in three series and eight other derivatives were designed and synthesized. Several novel synthetic methods for emodin nitroxide derivatives with mild reaction conditions, environmental friendliness, and high yields were established.

[0045] (2) The novel nitrogen oxide free radical derivatives of emodin provided by the present invention have low toxicity to normal liver cells, significant anti-proliferative activity against liver cancer cells, and are novel active molecules with better effects than emodin, providing a new idea for the preparation of anti-tumor drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0046] Figure 1 The effect of rhamnosine nitroxide derivative 8e on the migration ability of HepG2 cells;

[0047] Figure 2 The effect of the nitrogen oxide free radical derivative 8e of emodin on the cell cycle distribution of HepG2 cells;

[0048] Figure 3 Effects of emodin and its nitroxide derivatives on the morphology of HepG2 cells, where A represents the blank control group, and B represents the emodin and nitroxide derivatives 1e and 8e groups, the left image is at a magnification of 3000×, and the right image is at a magnification of 8000×;

[0049] Figure 4 The effect of emodin and its nitroxide derivatives on Fe 2+ The impact of levels;

[0050] Figure 5The effect of emodin and its nitroxide derivatives on the expression of MDA in HepG2 cells;

[0051] Figure 6 The effect of emodin and its nitroxide derivatives on GSH expression in HepG2 cells;

[0052] Figure 7 The effect of rhamnosyl nitroxide derivatives on ROS levels in HepG2 cells;

[0053] Figure 8 Figure 3 shows the effect of the rhamnosine nitroxide derivative 8e on the mRNA expression of SLC7A11 and GPX4. Figure A represents the effect on GPX4, and Figure B represents the effect on SLC7A11.

[0054] Figure 9 The effect of rhamnosine nitroxide derivative 8e on the expression of proteins xCT and GPX4 in HepG2 cells;

[0055] Note: Figures 4 to 6 、 Figures 8 and 9 Compared with the blank control group, *p<0.05, **p<0.01; in the figure, Control represents the blank control group, Sorafenib refers to sorafenib, and Emodin refers to emodin. DETAILED DESCRIPTION

[0056] In order to enable those skilled in the art to better understand the present invention, the present invention will be further explained in conjunction with specific embodiments.

[0057] Example 1

[0058] A rhamnolide nitroxide free radical derivative, wherein the rhamnolide nitroxide free radical derivative has a structure of general formula 1:

[0059]

[0060] The rhamnosine nitrogen oxide free radical derivative of general formula 1 is prepared by the following method:

[0061] (1) Rhamnosin and five bromoalcohols, namely 2-bromoethanol, 3-bromo-1-propanol, 4-bromo-1-butanol, 5-bromo-1-pentanol, and 6-bromo-1-hexanol, were used as raw materials, Cs2CO3 was used as a catalyst, and DMF was used as a solvent. The mixture was heated to 60°C and stirred under Ar gas for 9 hours. The solvent was then recovered by vacuum distillation, dissolved in water, and adjusted to pH = 5 with concentrated hydrochloric acid. The precipitate was filtered and washed with ethyl acetate to obtain powdery compounds, namely, rhamnosin derivative intermediates z1-z5 with different carbon chain lengths.

[0062] (2) The five intermediates and four carboxyl-containing nitrogen oxides such as 4-carboxyl-TEMPO were used as raw materials, EDCI and DMAP were used as catalysts, and DMF was used as solvent. The reaction was carried out at room temperature for 24 hours under the protection of Ar gas. The reaction solution was extracted with ethyl acetate, washed with water, dried over anhydrous Na2SO4, and separated by silica gel column chromatography to finally obtain the target compound.

[0063] Example 1-1

[0064] The only difference from Example 1 is:

[0065] (1) was heated to 50 °C under Ar gas protection and stirred for 9 h;

[0066] (2) The reaction was carried out at room temperature for 12 h under the protection of Ar gas.

[0067] The other steps are the same as those in Example 1.

[0068] Example 1-2

[0069] The only difference from Example 1 is:

[0070] (1) was heated to 70 °C under Ar gas protection and stirred for 9 h;

[0071] In (2), the reaction was carried out at room temperature for 18 h under the protection of Ar gas. The other steps were the same as those in Example 1.

[0072] Examples 1-3

[0073] The only difference from Example 1 is:

[0074] (2) was reacted at room temperature for 30 h under the protection of Ar gas. The other steps were the same as those in Example 1.

[0075] The conditions in Examples 1-1, 1-2, and 1-3 can also achieve the purpose of synthesizing the target product, but the highest yield among them is only about 45%. The yield of Example 1 is higher than that of Examples 1-1, 1-2, and 1-3, about 55%. Therefore, Example 1 is preferred as the reaction condition. Similarly, in the following examples, the reaction conditions with the highest yield are also selected as the reaction conditions, see Examples 2 and 3 for details.

[0076] The general formula 1 of the rhamnosine nitroxide free radical derivative obtained in Example 1 and the specific structures of the raw materials are shown in Table 1:

[0077] Table 1 Rheum nitroxide free radical derivatives general formula 1 and raw material structure

[0078]

[0079]

[0080]

[0081] Example 2

[0082] A rhamnolide nitroxide free radical derivative, wherein the rhamnolide nitroxide free radical derivative has a structure of general formula 2:

[0083]

[0084] The rhamnosine nitrogen oxide free radical derivative of general formula 2 is prepared by the following method:

[0085] (1) First, using emodin and propargyl bromide as raw materials, DMF as solvent, and anhydrous K2CO3 as catalyst, the reaction was heated to 70°C under the protection of Ar gas and magnetically stirred for 4 hours. TLC was used to detect the reaction until it was complete. The propargyl-substituted emodin derivative was obtained by extraction, washing, drying, and column chromatography separation and purification.

[0086] (2) Using propynyl-substituted rhamnosine derivatives, 4-formyl-TEMPO (e) and 3-formyl-2,2,5,5-tetramethylpyrrolidine-1-nitroxide free radical (f) and 20 secondary amines such as dipropylamine, 4-(trifluoromethyl)piperidine and morpholine as raw materials, toluene as solvent, CuBr as catalyst, under Ar gas protection, heating to 80 ° C and magnetic stirring for about 8 hours, TLC detection until the reaction is complete, column chromatography separation and purification, and finally the target compound was obtained.

[0087] Example 2-1

[0088] The only difference from Example 2 is that:

[0089] (1) Under the protection of Ar gas, the mixture was heated to 60 °C and magnetically stirred for 4 h;

[0090] (2) Under the protection of Ar gas, the mixture was heated to 60 °C and magnetically stirred for about 8 h.

[0091] Example 2-2

[0092] The only difference from Example 2 is that:

[0093] (1) Under the protection of Ar gas, the mixture was heated to 80 °C and magnetically stirred for 4 h;

[0094] (2) Under the protection of Ar gas, the mixture was heated to 80 °C and magnetically stirred for about 6 h.

[0095] Example 2-3

[0096] In (1), under the protection of Ar gas, the mixture was heated to 100°C and magnetically stirred for 4 h; in (2), under the protection of Ar gas, the mixture was heated to 60°C and magnetically stirred for about 7 h.

[0097] Examples 2-4

[0098] In (1), under the protection of Ar gas, the mixture was heated to 120°C and magnetically stirred for 4 h; in (2), under the protection of Ar gas, the mixture was heated to 60°C and magnetically stirred for about 6 h.

[0099] Examples 2-5

[0100] In (1), under the protection of Ar gas, the mixture was heated to 80°C and magnetically stirred for 4 h; in (2), under the protection of Ar gas, the mixture was heated to 80°C and magnetically stirred for about 6 h.

[0101] Examples 2-6

[0102] The only difference from Example 2 is that:

[0103] In (1), under the protection of Ar gas, the mixture was heated to 80°C and magnetically stirred for 4 h; in (2), under the protection of Ar gas, the mixture was heated to 80°C and magnetically stirred for about 7 h.

[0104] Examples 2-7

[0105] The only difference from Example 2 is that:

[0106] In (1), under the protection of Ar gas, the mixture was heated to 80°C and magnetically stirred for 4 h; in (2), under the protection of Ar gas, the mixture was heated to 100°C and magnetically stirred for about 6 h.

[0107] Examples 2-8

[0108] The only difference from Example 2 is that:

[0109] In (1), under the protection of Ar gas, the mixture was heated to 60°C and magnetically stirred for 4 h; in (2), under the protection of Ar gas, the mixture was heated to 120°C and magnetically stirred for about 6 h.

[0110] Examples 2-9

[0111] The only difference from Example 2 is that:

[0112] (1) Under the protection of Ar gas, the mixture was heated to 100 °C and stirred magnetically for 4 h;

[0113] (2) Under the protection of Ar gas, the mixture was heated to 60 °C and magnetically stirred for about 6 h.

[0114] Taking Example 2 as an example, the obtained rhamnosine nitrogen oxide free radical derivative general formula 2 and the specific structure of the raw materials are shown in Table 2 and Table 3:

[0115] Table 2 Rhamnosine propargylamine nitrogen oxide free radical derivatives general formula 2 and raw material structure

[0116]

[0117]

[0118]

[0119] Table 3 Rhamnosine propargylamine nitrogen oxide free radical derivatives general formula 2 and raw material structure

[0120]

[0121]

[0122]

[0123] Example 3

[0124] A rhamnolide nitroxide free radical derivative, wherein the rhamnolide nitroxide free radical derivative has the following structure:

[0125]

[0126] The rhamnosine nitrogen oxide free radical derivative of general formula 3 is prepared by the following method:

[0127] Four carboxyl-containing nitrogen oxide free radicals, including emodin and 4-carboxyl-TEMPO, were used as raw materials, DMF was used as solvent, EDCI and DMAP were used as catalysts, and the reaction was magnetically stirred at room temperature for 7 hours under Ar gas protection. TLC tracking and monitoring was carried out until the reaction was complete. After terminating the reaction, the target compound was finally obtained by extraction, washing, drying and filtration, and separation and purification by silica gel column chromatography.

[0128] Example 3-1

[0129] The only difference from Example 3 is that:

[0130] The reaction was carried out under magnetic stirring at room temperature for 5 h under Ar gas protection. The other steps were the same as those in Example 3.

[0131] Example 3-2

[0132] The reaction was carried out under magnetic stirring at room temperature under Ar gas protection for 9 h. The other steps were the same as those in Example 3.

[0133] Example 3-3

[0134] The reaction was carried out under magnetic stirring at room temperature for 12 h under Ar gas protection. The other steps were the same as those in Example 3.

[0135] The general formula 3 of the rhamnosine nitrogen oxide free radical derivative obtained in Example 3 and the specific structures of the raw materials are shown in Table 4:

[0136] Table 4 Rhamnosine nitrogen oxide free radical derivatives general formula 3 and raw material structure

[0137]

[0138] Test Example 1 Evaluation of the Anti-liver Cancer Activity of Nitrogen Oxygen Free Radical Derivatives of Emodin

[0139] The MTT method was used to determine the anti-proliferative activity of nitroxide free radicals, emodin and its nitroxide free radical derivatives on liver cancer cells and the cytotoxicity on normal cells L02 in Examples 1, 2 and 3. The results are shown in Table 5:

[0140] Table 5 Antiproliferative activity of nitroxide free radicals, emodin and its nitroxide free radical derivatives on liver cancer cells and cytotoxicity on normal cells L02

[0141]

[0142]

[0143] As shown in Table 5, the six nitroxide free radicals and emodin all showed good anti-proliferative activity against HepG2 liver cancer cells. 50 The values ​​were between 25.40 and 50.01 μM, and the IC 50 The value was 59.55 μM. The anti-proliferative ability of the new rhamnosin nitroxide free radical derivatives was different. There were 31 new compounds with IC values ​​of 1. 50 The value was less than 59.55 μM, and the anti-proliferative ability was significantly improved compared with that of flavin. The IC values ​​of 5 new compounds such as 1e and 8e were 50 The value was lower than 10 μM, showing good anti-proliferative activity. Cytotoxicity results showed that 26 of the 31 novel compounds had IC values ​​of 0. 50 Rheum officinale

[0144] (IC 50 =44.63 μM), showing low toxicity, and their selectivity index SI was greater than that of emodin (0.75). The selectivity indexes of derivatives 1e and 8e were 8.13 and 14.87, respectively, showing good selective anti-liver cancer cell proliferation activity. The low-toxic and significantly active anti-liver cancer active molecules 1e and 8e were screened out.

[0145] The results of cell wound healing experiments showed that emodin and its derivatives 1e and 8e had a certain inhibitory effect on the migration and repair of liver cancer cells HepG2, and showed a dose-dependent effect. The results of cell cycle experiments showed that emodin and its derivatives 1e and 8e could block HepG2 cells in the G1 / S phase in a dose-dependent manner, thereby exerting anti-tumor activity. Figures 1 and 2 As shown in Tables 6 and 7.

[0146] Table 6 Effects of rhamnosine nitroxide derivative 8e on the migration ability of HepG2 cells

[0147]

[0148] Table 7 Effects of rhamnosine nitroxide derivative 8e on HepG2 cell cycle distribution

[0149]

[0150]

[0151] Experimental Example 2 Study on the Anti-liver Cancer Mechanism of Nitrogen Oxygen Free Radical Derivatives of Emodin

[0152] Transmission electron microscopy revealed that the mitochondrial morphology of liver cancer cells in each group changed significantly after intervention with emodin and its nitroxide free radical derivatives 1e and 8e, with the manifestation of reduced volume, increased double membrane density, and reduced mitochondrial cristae, which are consistent with the characteristics of mitochondrial ferroptosis. The higher the concentration, the more obvious the changes. Figure 3 By measuring the Fe 2+ , MDA, GSH and ROS levels in HepG2 cells. Compared with the blank control group, emodin and its nitroxide free radical derivatives 1e and 8e could significantly increase the intracellular Fe 2+ , MDA and ROS levels (p<0.01), and reduced GSH level (p<0.01), and showed a dose-dependent manner. Figures 4 to 7 As shown in Table 8 (Control represents the blank control group, Sorafenib refers to sorafenib, and Emodin refers to emodin). RT-qPCR and WB results showed that SLC7A11 and GPX4 were expressed in HepG2 cells, and the mRNA and protein expression levels of SLC7A11 and GPX4 were significantly decreased after drug intervention (p < 0.01). Figures 8 and 9 As shown in Table 9, the effects of the nitrogen oxide free radical derivatives 1e and 8e of emodin were more significant than those of emodin.

[0153] Table 8 Effects of emodin and its nitroxide derivative 8e on Fe in HepG2 cells 2+levels, MDA expression in HepG2 cells, GSH expression in HepG2 cells, and ROS levels in HepG2 cells

[0154]

[0155] Table 9 Effects of the nitrogen oxide derivative 8e of emodin on the expression of SLC7A11 and GPX4 mRNA and the expression of proteins xCT and GPX4 in HepG2 cells

[0156]

[0157] As can be seen from Tables 8 and 9, rhamnosine nitroxide derivatives 1e and 8e downregulate SLC7A11 by inhibiting System Xc-, reducing the uptake of intracellular cystine, resulting in reduced GSH synthesis, indirectly inhibiting the activity of GPX4, inducing abnormal accumulation of lipid ROS, and simultaneously upregulating Fe2+ levels, ultimately leading to ferroptosis of liver cancer cells.

Claims

1. A nitrogen oxide free radical derivative of rhamnosus, characterized in that: The structural formula of the rhamnosine nitrogen oxide free radical derivative is selected from any one of the following:

2. The method for synthesizing the rhamnoic acid nitroxide derivative according to claim 1, comprising the steps of: Using emodin and bromohydrin as raw materials, Cs2CO3 as a catalyst, and DMF as a solvent, the mixture is heated to 50-70°C under Ar gas protection and subjected to constant temperature reaction for 8-10 hours, followed by reduced pressure distillation to recover the solvent, which is then dissolved with water and the pH is adjusted to less than 7 with acid. After precipitation, the precipitate is filtered and washed with ethyl acetate to obtain an emodin derivative intermediate with carbon chain substitution of different lengths; then, the intermediate and a carboxyl-containing nitroxide free radical are used as raw materials, EDCI and DMAP as catalysts, and DMF as a solvent, the mixture is reacted at room temperature under Ar gas protection, the reaction liquid is extracted with ethyl acetate, washed with water, dried, and chromatographically separated to finally obtain an emodin nitroxide free radical derivative having the structure described in claim 1; The bromoalcohol is selected from any one of 2-bromoethanol, 3-bromo-1-propanol, 4-bromo-1-butanol, 5-bromo-1-pentanol and 6-bromo-1-hexanol; The carboxyl-containing nitroxide radical is selected from any one of Formulas 1 to 4:

3. The use of the rhamnosine nitroxide free radical derivative according to claim 1 in the preparation of anti-tumor drugs, characterized in that: The anti-tumor drug is an anti-liver cancer drug.

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