Glycosylated quercetin amphiphilic prodrug as well as preparation method and application thereof

Abstract

The invention discloses a glycosylated quercetin amphiphilic prodrug, a preparation method and application of the glycosylated quercetin amphiphilic prodrug. The glycosylated quercetin amphiphilic prodrug, the preparation method of the glycosylated quercetin amphiphilic prodrug and the application of the glycosylated quercetin amphiphilic prodrug are included. According to the glycosylated quercetin amphiphilic prodrug as well as the preparation method and the application thereof, the pH-sensitive glycosylated quercetin amphiphilic prodrug is obtained through parallel connection of the boric acid ester and the hydrophilic targeting sugar molecule lactobionic acid and the hydrophobic quercetin, and the pH-sensitive glycosylated quercetin amphiphilic prodrug and clinical common anti-tumor drugs are further assembled into a nano-drug; the invention aims at improving the physicochemical / pharmacological activity of quercetin and exploring the anti-tumor effect of quercetin cooperating with clinical drugs at the same time. The glycosylated quercetin amphiphilic prodrug is designed according to a drug combination principle, a formula 3 is used as a substrate, molecular quercetin is combined to obtain the glycosylated quercetin amphiphilic prodrug, and pH-sensitive borate bonds are introduced, so that drug release and tumor resistance can be controlled, the drug has certain targeting property, and the biological activity is remarkably improved.

Description

Technical Field

[0001] The invention belongs to the technical field of prodrug carriers and drug controlled release, and specifically relates to a glycosylated quercetin amphiphilic prodrug, a preparation method and an application thereof. Background Art

[0002] As a polyhydroxyflavonoid compound, quercetin is an important active ingredient in many traditional Chinese medicines. It has extremely high medicinal value and has been widely studied in the field of anti-tumor drugs. Quercetin can significantly inhibit the effects of cancer promoters and inhibit the synthesis of DNA, RNA and protein in cancer cells. The molecular mechanism of quercetin's anti-tumor effect is complex, and it can inhibit tumor growth through various pathways, such as affecting mitochondrial integrity, disrupting the dynamic balance of reactive oxygen species (ROS), inhibiting β-catenin nuclear translocation, and blocking the conduction of the Wnt signaling pathway. However, quercetin is highly hydrophobic, and organic solvents are required when preparing solutions. At the same time, the phenolic hydroxyl groups in the structure are easily oxidized. These factors limit the in vivo use of quercetin, resulting in its loss of clinical development value.

[0003] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention and should not be regarded as an acknowledgment or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art. Summary of the invention

[0004] The object of the present invention is to provide a glycosylated quercetin amphiphilic prodrug, a preparation method and application thereof, which can solve the technical problems raised in the above background technology.

[0005] In order to achieve the above object, a technical solution provided by a specific embodiment of the present invention is as follows:

[0006] A glycosylated quercetin amphiphilic prodrug comprising a pH-sensitive boronate ester bond and a targeting sugar molecule;

[0007] The structure of the glycosylated quercetin amphiphilic prodrug is shown in the structural formula:

[0008]

[0009] In order to achieve the above object, a technical solution provided by a specific embodiment of the present invention is as follows:

[0010] A method for preparing a glycosylated quercetin amphiphilic prodrug, wherein the synthesis route of the glycosylated quercetin amphiphilic prodrug is as follows:

[0011]

[0012] In one or more embodiments of the present invention, the following steps are included:

[0013] Add lactobionic acid of formula 1 and aminophenylboronic acid of formula 2 to a reaction bottle, then add catalyst EDC / NHS, use water as solvent, stir at room temperature for reaction for 20 to 28 hours, concentrate and precipitate with glacial ether to obtain product formula 5, add the compound shown in formula 3 and quercetin shown in formula 4 to the reactor, add anhydrous DMSO as solvent, and use dried sodium sulfate as a water-binding agent, stir at room temperature for 10 to 14 hours, dialyze the reaction solution with a dialysis bag, and then freeze-dry to obtain a crude product, which is then separated and purified by column chromatography to obtain a glycosylated quercetin prodrug as shown in formula 3.

[0014] In one or more embodiments of the present invention, the reaction molar ratio of Formula 1, Formula 2 and the catalyst is (1:1.5:3:3) to (1:2:5:5).

[0015] In one or more embodiments of the present invention, the reaction molar ratio of Formula 3, Formula 4 and sodium sulfate is (0.8:0.8.5:0.1) to (1.2:1.2:0.3).

[0016] In one or more embodiments of the present invention, the reaction molar ratio of Formula 3, Formula 4 and sodium sulfate is (0.8:0.8.5:0.1) to (1.2:1.2:0.3).

[0017] In one or more embodiments of the present invention, the molecular weight cut-off of the dialysis bag is 200-300 Da, and the dialysis bag contains a dialysis fluid, which is deionized water with a pH value of 5.0-10.0.

[0018] In one or more embodiments of the present invention, the column chromatography is a gel column, and the eluent used to elute the gel column includes methanol and dichloromethane;

[0019] The ratio of methanol to dichloromethane is (1:0.5) to (3:1.5).

[0020] In order to achieve the above object, a technical solution provided by a specific embodiment of the present invention is as follows:

[0021] Application of a glycosylated quercetin amphiphilic prodrug in the preparation of small molecule prodrug anti-tumor nanocarriers.

[0022] In one or more embodiments of the present invention, the small molecule prodrug anti-tumor nanocarrier includes glycosylated quercetin of formula 5 and an anti-tumor drug, and the anti-tumor drug includes one or more combinations of doxorubicin, paclitaxel, camptothecin, and cisplatin.

[0023] Compared with the prior art, the present invention provides a glycosylated quercetin amphiphilic prodrug, preparation method and application thereof, which obtains a pH-sensitive glycosylated quercetin amphiphilic prodrug by linking a hydrophilic targeting sugar molecule lactobionic acid and a hydrophobic quercetin through borate, and further co-assembles the prodrug with common clinical anti-tumor drugs into a nano-drug, aiming to enhance the physicochemical / pharmacological activity of quercetin, and at the same time explore the anti-tumor effect of quercetin in synergy with clinical drugs;

[0024] According to the drug ligation principle, formula 3 is used as a substrate, and a quercetin molecule is ligated to obtain a glycosylated quercetin amphiphilic prodrug. In the glycosylated quercetin amphiphilic prodrug molecule disclosed in the present invention, a pH-sensitive boronate bond is introduced to control the release of the drug, which has anti-tumor effect, makes the drug have a certain targeting, and significantly improves the biological activity. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments recorded in the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0026] Figure 1 is an infrared spectrum of a glycosylated quercetin amphiphilic prodrug in one embodiment of the present invention;

[0027] Figure 2 The particle size and distribution of the glycosylated quercetin amphiphilic prodrug in one embodiment of the present invention;

[0028] Figure 3 is the potential of the glycosylated quercetin amphiphilic prodrug in one embodiment of the present invention;

[0029] Figure 4 This is a scanning electron micrograph of a glycosylated quercetin amphiphilic prodrug in one embodiment of the present invention;

[0030] Figure 5 This is a transmission electron micrograph of a glycosylated quercetin amphiphilic prodrug in one embodiment of the present invention;

[0031] Figure 6 This is a diagram showing the hydrophilicity and hydrophobicity test results of the glycosylated quercetin amphiphilic prodrug in one embodiment of the present invention;

[0032] Figure 7 This is a graph showing the in vitro drug release results of quercetin from a glycosylated quercetin amphiphilic prodrug in one embodiment of the present invention;

[0033] Figure 8 This is a diagram showing the cytotoxicity test results of quercetin in one embodiment of the present invention;

[0034] Fig. 9 This is a result diagram of the cell targeting effect of the amphiphilic prodrug of glycosylated quercetin in one embodiment of the present invention;

[0035] Fig.10 This is a graph showing the XPS detection results of the glycosylated quercetin amphiphilic prodrug and cisplatin chelation in one embodiment of the present invention. DETAILED DESCRIPTION

[0036] In order to enable those skilled in the art to better understand the technical solutions in the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work should fall within the scope of protection of the present invention.

[0037] A glycosylated quercetin amphiphilic prodrug in one embodiment of the present invention includes a pH-sensitive boronate bond and a targeted sugar molecule. As one of the basic substances of a living body, the sugar molecule participates in almost all processes of life, and the derived glycosylation products are particularly involved in the regulation of various diseases, such as immune system diseases, infectious diseases, cancer, inflammation, etc. Studies have shown that the glycosyl moiety can change the pharmacological activity of the parent drug by increasing solubility, regulating plasma half-life, and improving the specificity of binding to the site of action. Therefore, glycosylation is widely used in the transformation of drugs and has become a common means of structural modification and modification of drugs (such as polypeptides, alkaloids, and polyphenols, etc.). In particular, some carbohydrate molecules can specifically recognize the specific binding receptors present on the cell surface and transmit the drug in a targeted manner, which can achieve a targeted delivery effect, such as glucose, galactose, mannose, etc. Therefore, the design and synthesis of biologically active groups or lead compounds into glycosylated derivatives can optimize the pharmacological activity or mode of action of drug molecules, which is conducive to obtaining new drugs with high bioavailability.

[0038] In addition, the microenvironment of the tumor site is quite different from that of normal tissues, such as overexpression of enzymes, pH gradient, excessive oxides (such as H2O2) and glutathione (GSH). Taking advantage of these microenvironmental differences, stimulus-responsive chemical bonds, such as orthoesters, disulfide bonds, borate esters, etc., can be introduced during drug modification or material preparation. This design is conducive to shielding the active sites of drugs in the physiological environment, while completing drug dissociation and release in response to stimuli in the tumor microenvironment, exerting the pharmacological activity of the drug, and ultimately achieving specific killing of tumor cells.

[0039] Specifically, the glycosylated quercetin amphiphilic prodrug is shown in the following structure:

[0040]

[0041] The present invention also discloses a method for preparing the above-mentioned glycosylated quercetin amphiphilic prodrug. The synthesis route of the glycosylated quercetin amphiphilic prodrug is as follows:

[0042]

[0043] Add lactobionic acid of formula 1 and aminophenylboronic acid of formula 2 to a reaction bottle, then add catalyst EDC / NHS, use water as solvent, stir at room temperature for 20 to 28 hours, concentrate and precipitate with ice ether to obtain product formula 5, i.e. LA-PBA. Add the compound shown in formula 3 and quercetin shown in formula 4 to a reactor, add anhydrous DMSO as solvent, and use dried sodium sulfate as a water-binding agent, stir at room temperature for 10 to 14 hours, dialyze the reaction solution with a dialysis bag, and then freeze-dry to obtain a crude product, which is then separated and purified by column chromatography to obtain a glycosylated quercetin prodrug as shown in formula 3, i.e. LA-PBA-QC.

[0044] The reaction molar ratio of Formula 3, Formula 4 and sodium sulfate is (0.8:0.8.5:0.1) to (1.2:1.2:0.3). The molecular weight cut-off of the dialysis bag is 200 to 300 Da, and the dialysis bag contains a dialysate, which is deionized water with a pH value of 5.0 to 10.0. The reaction molar ratio of Formula 1, Formula 2 and the catalyst is (1:1.5:3:3) to (1:2:5:5).

[0045] The present invention also discloses the use of the above-mentioned glycosylated quercetin amphiphilic prodrug in the preparation of small molecule anti-tumor nanocarriers. The small molecule prodrug anti-tumor nanocarriers include the glycosylated quercetin amphiphilic prodrug as shown in Formula 5 and anti-tumor drugs, and the anti-tumor drugs are but not limited to small molecule drugs such as doxorubicin, paclitaxel, camptothecin, cisplatin, etc.

[0046] Specifically, Figure 1 As shown, lactobionic acid of formula 1 and aminophenylboronic acid of formula 2 are added to a reaction bottle, and then catalyst EDC / NHS is added. Water is used as solvent, and the reaction is stirred at room temperature for 24 hours. After concentration, it is precipitated with ice ether to obtain the product of formula 5, i.e. LA-PBA. Then the compound shown in formula 3 and quercetin shown in formula 4 are added to the reactor, anhydrous DMSO is added as solvent, and dried sodium sulfate is used as a water-binding agent. Stir at room temperature for 12 hours. The reaction solution is dialyzed with a dialysis bag, and then freeze-dried to obtain a crude product, which is then separated and purified by column chromatography to obtain a glycosylated quercetin prodrug as shown in formula 3, i.e. LA-PBA-QC. The obtained prodrug and its raw materials are mixed with KBr and pressed into tablets, and then Fourier infrared spectroscopy is performed. The results are as shown Figure 1 shown.

[0047] In quercetin alone, 3400 cm -1 Nearby is its OH absorption peak, 1726cm -1is the C=O stretching vibration absorption peak. In LA-PBA, 1552cm -1 and 1623cm -1 is the amide stretching vibration absorption peak, indicating that LA and PBA have undergone amide condensation reaction. -1 The C=O characteristic peak of quercetin and the amide characteristic peak of LA-PBA also appeared. -1 The characteristic absorption peak of borate ester appears at 1350cm -1 and 1427cm -1 The symmetric and asymmetric stretching vibration peaks of BO appeared at , indicating that boronate ester was generated between LA-PBA and QC. In summary, the boronate ester-coupled glycosylated quercetin prodrug was successfully synthesized.

[0048] like Figure 2-3 As shown, 30 mg of LA-PBA-QC was weighed and dissolved in 1 mL of dimethyl sulfoxide, deionized water was slowly added dropwise while stirring, and then ultrasonic cell disruptor was used for 1 min, and then the solution was dialyzed for 12 h, during which the deionized water was replaced every 4 h to obtain the prodrug self-assembled nanoparticles LA-PBA-QC / NPs.

[0049] The glycosylated quercetin amphiphilic prodrug nanoparticles were dispersed in 0.01M PB buffer at pH 8.0, 1 mL of the nanoparticle emulsion was diluted to an appropriate concentration, and the particle size and distribution were measured by DLS at room temperature. Figure 2 The results of three tests showed that the average particle size of the prodrug particles was about 358.13±33.16 nm.

[0050] The glycosylated quercetin amphiphilic prodrug nanoparticles were dispersed in 0.01M PB buffer at pH 8.0. 1 mL of the nanoparticle emulsion was diluted to an appropriate concentration and its potential was measured by DLS at room temperature. Figure 3 As shown in Figure 2, the average surface charge of the prodrug particles was 0.98±0.09 mV after three tests.

[0051] like Figure 4-5 As shown, 100 μL of the nanoparticle emulsion in Example 2 was taken, 2 to 3 times the volume of deionized water was added to obtain a diluent, 10 μL of the diluent was taken by a pipette and dropped onto a silicon wafer, and after drying and spraying with gold, the morphology was observed by a scanning electron microscope. The results are as follows Figure 4 Similarly, 10 μL of the dilution solution was added to the copper grid, and after drying, its morphology was observed using a transmission electron microscope. The results are shown in Figure 5As shown. SEM electron microscopy shows that the prodrug particles are spherical, a small number of particles are larger in size, and most are about 150nm. TEM electron microscopy shows that the center of the prodrug particles is darker in color and the surrounding color is lighter, indicating that the inside is hydrophobic quercetin and the surrounding is hydrophilic lactobionic acid.

[0052] like Figure 6 As shown in the figure, the nanoparticle emulsion was freeze-dried in a vacuum, and about 30 mg of sample powder was added to the groove of the XRD diffractometer. It was compacted with a glass slide and the surface was made as flat as possible. Then it was placed on the stage of the contact angle meter, and 2 μL of deionized water was squeezed out from the outlet of the micro-injector. The descending speed was controlled so that the droplet slowly approached the sample, and the test process was photographed at a speed of 30 frames / second. The results are shown in the figure. Figure 4 It can be found that the contact angle of pure quercetin is about 110°, while the contact angle of the glycosylated pre-drug solution is about 90°, indicating that glycosylation effectively improves the hydrophilicity of quercetin.

[0053] like Figure 7 As shown, take 1mL of glycosylated quercetin amphiphilic prodrug nanoparticle emulsion (drug concentration is 500μg / mL), place it in a dialysis bag with a molecular weight cutoff of 8-14kD, tie the two ends with cotton thread, put it into a 50mL EP tube, and add 5mL of buffer solution of different pH. Oscillate at 37°C and 100rpm, and at set time intervals such as 0.5, 1, 2, 3, 4, 6...48h, aspirate the old buffer solution and store it, add new buffer solution, and set three parallel groups for each sample. Finally, the concentration of quercetin in the release medium was detected at a wavelength of 364nm, and the cumulative quercetin release was calculated according to the standard curve. The results are shown in Figure 5 The drug release was the lowest at pH 7.4, while the cumulative release reached 90% at pH 5.5 after 48 h, indicating that the prodrug particles were sensitive to weak acid and had pH stimulus responsiveness.

[0054] like Figure 8 Mouse breast cancer cells (4T1) were added to a 96-well plate, with 5×10 cells per well. 3 After 24 hours of co-culture, the old culture medium was removed, and 180 μL of culture medium and 20 μL of quercetin or prodrug nanoparticles of different concentrations were added to each duplicate well, and a blank group and a negative control were set. After 24 hours of co-culture, the old culture medium was removed, and 20 μL of MTT (5 mg / mL) was added to each duplicate well. After incubation for 4 hours, the liquid was finally removed, and 150 μL of DMSO was added to each duplicate well. The cell viability was measured under the condition of a microplate reader wavelength of 570 nm. The results are shown in FIG. Figure 6As shown in Figure 2, both QC solution and prodrug particles showed dose-dependent cell-killing toxicity in 4T1 cells. In addition, the cytotoxicity of prodrug particles was significantly stronger than that of QC solution, which was attributed to its good hydrophilicity and sugar targeting.

[0055] like Fig. 9 As shown, cisplatin was replaced with coumarin C6 to obtain C6-loaded nanoparticles LA-PBA-QC / C6-NPs. Mouse breast cancer cells (4T1) were then added to the cell culture dish and cultured for 24 hours. After the cells adhered, they were co-incubated with LA-PBA-QC / C6-NPs for 4 hours. The old cell culture medium was then removed and the cells were washed several times with PBS. After washing, a 4% paraformaldehyde solution was added to fix the cells for 10 minutes. The cells were washed again and the nuclei were stained with DAPI for 10 minutes. After washing, the cells were observed and photographed using a confocal microscope. In addition, before co-culture, 100 μL of 5 mg / mL lactobionic acid was added to the cells in advance and incubated for 0.5 hours, and then co-cultured with LA-PBA-QC / C6-NPs to observe the cell uptake. The results are shown in the figure. Figure 7 It can be found that the fluorescently loaded prodrug particles exhibit obvious green fluorescence in the cells. When pre-incubated with LA, the intracellular fluorescence intensity is significantly reduced, indicating that the prodrug particles enter the cells through the LA receptor-mediated endocytosis pathway.

[0056] like Fig.10 As shown, 30 mg of LA-PBA-QC was weighed and dissolved in 1 mL of dimethyl sulfoxide (5 mg / mL cisplatin), and deionized water was slowly added dropwise while stirring. Then, an ultrasonic cell disruptor was used for 1 min, and the solution was dialyzed for 12 h. During this period, deionized water was replaced every 4 h to obtain a cisplatin nanoparticle LA-PBA-QC / Pt-NPs solution. The powder obtained by freeze-drying was subjected to XPS analysis. The results are shown in FIG. Figure 8 In the XPS full spectrum and Pt spectra, obvious Pt chemical bond energy absorption peaks can be found, suggesting that the prodrug particles can bind to cisplatin, and the possible binding site is the formation of hydrogen bonds between the phenolic hydroxyl group of quercetin and cisplatin.

[0057] The present invention obtains a pH-sensitive glycosylated quercetin amphiphilic prodrug by linking the hydrophilic targeting sugar molecule lactobionic acid and the hydrophobic quercetin through borate ester, and further co-assembles it with common clinical anti-tumor drugs (such as doxorubicin, cisplatin, paclitaxel, etc.) into a nanodrug, aiming to enhance the physicochemical / pharmacological activity of quercetin and explore the anti-tumor effect of quercetin in synergy with clinical drugs.

[0058] The present invention is designed according to the drug ligation principle to use Formula 3 as a substrate, and obtains a glycosylated quercetin amphiphilic prodrug after ligation of a quercetin molecule. In the glycosylated quercetin amphiphilic prodrug molecule disclosed by the present invention, by introducing a pH-sensitive boronate bond (the compound shown in Formula 5), ​​the drug can be controlled to release and resist tumors, so that the drug has a certain targeting and significantly improves the biological activity.

[0059] It will be apparent to those skilled in the art that the invention is not limited to the details of the exemplary embodiments described above and that the invention can be implemented in other specific forms without departing from the spirit or essential features of the invention. Therefore, the embodiments should be considered exemplary and non-limiting in all respects, and the scope of the invention is defined by the appended claims rather than the foregoing description, and it is intended that all variations falling within the meaning and scope of the equivalent elements of the claims be included in the invention. Any reference numeral in a claim should not be considered as limiting the claim to which it relates.

[0060] In addition, it should be understood that although the present specification is described according to implementation modes, not every implementation mode contains only one independent technical solution. This description of the specification is only for the sake of clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment may also be appropriately combined to form other implementation modes that can be understood by those skilled in the art.

Claims

1. A glycosylated quercetin amphiphilic prodrug, characterized in that: Includes pH-sensitive boronate ester bonds and targeted sugar molecules; The structure of the glycosylated quercetin amphiphilic prodrug is shown in the structural formula:

2. A method for preparing a glycosylated quercetin amphiphilic prodrug, characterized in that: The synthetic route of the glycosylated quercetin amphiphilic prodrug is as follows:

3. The method for preparing a glycosylated quercetin amphiphilic prodrug according to claim 2, characterized in that: The following steps are involved: Add lactobionic acid of formula 1 and aminophenylboronic acid of formula 2 into a reaction bottle, then add catalyst EDC / NHS, use water as solvent, stir at room temperature for 20 to 28 hours, concentrate and precipitate with glacial ether to obtain product of formula 5; The compound shown in Formula 3 and the quercetin shown in Formula 4 are added to a reactor, anhydrous DMSO is added as a solvent, and dried sodium sulfate is used as a water-binding agent. The mixture is stirred at room temperature for 10 to 14 hours. The reaction solution is dialyzed using a dialysis bag, and then freeze-dried to obtain a crude product, which is then separated and purified by column chromatography to obtain a glycosylated quercetin prodrug as shown in Formula 3.

4. The method for preparing a glycosylated quercetin amphiphilic prodrug according to claim 2 or 3, characterized in that: The reaction molar ratio of Formula 1, Formula 2 and the catalyst is (1:1.5:3:3) to (1:2:5:5).

5. The method for preparing a glycosylated quercetin amphiphilic prodrug according to claim 2 or 3, characterized in that: The reaction molar ratio of Formula 3, Formula 4 and sodium sulfate is (0.8:0.8:0.1) to (1.2:1.2:0.3).

6. The method for preparing a glycosylated quercetin amphiphilic prodrug according to claim 4, characterized in that: The reaction molar ratio of Formula 3, Formula 4 and sodium sulfate is (0.8:0.8.5:0.1) to (1.2:1.2:0.3).

7. The method for preparing a glycosylated quercetin amphiphilic prodrug according to claim 3, characterized in that: The molecular weight cut-off of the dialysis bag is 200-300 Da. The dialysis bag contains a dialysis solution, which is deionized water with a pH value of 5.0-10.

0.

8. The method for preparing a glycosylated quercetin amphiphilic prodrug according to claim 3, characterized in that: The column chromatography is a gel column, and the eluent used to elute the gel column includes methanol and dichloromethane; The ratio of methanol to dichloromethane is (1:0.5) to (3:1.5).

9. Application of a glycosylated quercetin amphiphilic prodrug in the preparation of small molecule anti-tumor nanomedicine.

10. The use of a glycosylated quercetin amphiphilic prodrug according to claim 9 in the preparation of small molecule prodrug anti-tumor nanocarriers, characterized in that: The small molecule prodrug anti-tumor nanocarrier comprises glycosylated quercetin of formula 5 and an anti-tumor drug; The anti-tumor drug includes one or more combinations of doxorubicin, paclitaxel, camptothecin and cisplatin.

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