Thiotriptolide derivatives, and preparation method, pharmaceutical composition and application thereof

Abstract

The invention belongs to the field of natural medicines and medicinal chemistry, and discloses a thiotriptolide derivative and a preparation method, a pharmaceutical composition and application thereof. Specifically, the invention discloses a thiotriptolide derivative shown as a general formula I and a general formula II. The derivatives are prepared in an artificial synthesis mode, pharmaceutical compositions containing the derivatives, and uses of the derivatives in preparation of drugs for treating tumor diseases.

Description

Technical Field

[0001] This invention belongs to the field of natural medicines and medicinal chemistry, specifically relating to a class of thiotriptylide alcohol derivatives. This invention also discloses methods for preparing such derivatives, pharmaceutical compositions, and their uses in antitumor applications. Background Technology

[0002] Tripterygium wilfordii is a traditional Chinese herbal medicine with relatively abundant resources in my country. Its main active ingredient, triptolide, is a rosinane-type diterpenoid compound containing three epoxy groups and one α,β-unsaturated five-membered lactone ring, exhibiting significant anti-inflammatory, anti-tumor, immunosuppressive, and anti-male fertility activities. Since its discovery, it has attracted widespread attention from medicinal chemists and pharmacologists. However, its high toxicity limits its clinical application. Therefore, improving the safety window of such compounds while maintaining clinical efficacy is currently a bottleneck in research and development in this field.

[0003] The principle of bioisosterism involves replacing certain atoms or groups in a compound's structure with atoms or groups that have the same total number of outer electrons (same valence) or similarity in important parameters such as volume, shape, conformation, electron distribution, lipid-water partition coefficient pKa, chemical reactivity, and hydrogen bond formation ability, resulting in new compounds. The principle of bioisosterism is one of the effective strategies for the rational optimization of lead compounds. Replacing O atoms with S atoms is a common method of structural modification using the principle of bioisosterism, often exhibiting synergistic effects and reducing toxicity, thus attracting considerable attention in new drug research. Therefore, based on the principle of bioisosterism, we replaced the O at position 18 of triptolide with S to obtain a novel antitumor drug with an expanded safety window. Summary of the Invention

[0004] The purpose of this invention is to obtain novel antitumor drugs with expanded safety windows by replacing the 18-position O with S through bio-electron isochoricization of triptolide and triptolide alcohol.

[0005] Another object of the present invention is to provide a method for preparing the above-mentioned compound.

[0006] A further object of the present invention is to provide the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof.

[0007] The objective of this invention can be achieved through the following measures:

[0008] Compounds having the structure of Formula I or their pharmaceutically acceptable salts,

[0009]

[0010] R1 is selected from H or OH.

[0011] The compound represented by general formula I of this invention can be prepared by the following method: triptolide ketone is converted into sulfur by Lawesson reagent to convert the carbonyl oxygen in the five-membered lactone ring to obtain STP-1; then, by oxidation with selenium dioxide, a hydroxyl group is introduced at position 19 to obtain STP-4.

[0012]

[0013] Condition a: reactant is Lawesson's reagent, solvent is toluene, and reaction is carried out under reflux; Condition b: reactant is selenium dioxide, solvent is dioxane, and reaction is carried out at 100°C.

[0014] Compounds having the structure of formula II or their pharmaceutically acceptable salts,

[0015]

[0016] R2 is selected from H or OH;

[0017] R3 is selected from H or OH;

[0018] R4 is selected from H or OH.

[0019] The compounds represented by general formula II of this invention can be prepared by the following methods: STP-1 is oxidized with sodium borohydride to obtain STP-2 and STP-3; STP-4 is oxidized with sodium borohydride to obtain STP-5 and STP-6.

[0020]

[0021] Among them, condition a: reactant NaBH4, solvent is methanol, reaction at room temperature.

[0022] Another aspect of the present invention relates to pharmaceutical compositions using the compounds of the present invention as active ingredients. These pharmaceutical compositions are prepared according to methods known in the art. They can be formulated into any dosage form suitable for human or animal use by combining the compounds of the present invention with one or more pharmaceutically acceptable solid or liquid excipients and / or adjuvants. The compounds of the present invention are typically present in pharmaceutical compositions at a weight content of 0.1-95%.

[0023] The compounds of this invention or pharmaceutical compositions containing them can be administered in unit dose form via enteral or non-enteric routes, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum, etc.

[0024] Dosage forms can be liquid, solid, or semi-solid. Liquid dosage forms can include solutions (including true solutions and colloidal solutions), emulsions (including o / w, w / o, and double emulsions), suspensions, injections (including aqueous injections, powder injections, and infusions), eye drops, nasal drops, lotions, and liniments, etc.; solid dosage forms can include tablets (including regular tablets, enteric-coated tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, and orally disintegrating tablets), capsules (including hard capsules, soft capsules, and enteric-coated capsules), granules, powders, microcapsules, pellets, suppositories, films, patches, aerosols, and sprays, etc.; semi-solid dosage forms can include ointments, gels, and pastes, etc.

[0025] The compounds of this invention can be formulated into conventional formulations, sustained-release formulations, controlled-release formulations, targeted formulations, and various microparticle delivery systems.

[0026] To formulate the compounds of the present invention into tablets, a wide variety of excipients known in the art can be used, including diluents, binders, wetting agents, disintegrants, lubricants, and flow aids. Diluents can be starch, dextrin, sucrose, glucose, lactose, mannose, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, dicalcium phosphate, calcium carbonate, etc.; wetting agents can be water, ethanol, isopropanol, etc.; binders can be starch paste, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, gum arabic paste, gelatin paste, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; disintegrants can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfonate, etc.; lubricants and flow aids can be talc, silica, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc.

[0027] Tablets can also be further processed into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or bilayer and multilayer tablets.

[0028] To formulate the drug delivery unit into capsules, the active ingredient, the compound of the present invention, can be mixed with a diluent and a disintegrant, and the mixture can be placed directly into hard or soft capsules. Alternatively, the active ingredient, the compound of the present invention, can be first formed into granules or microspheres with a diluent, binder, and disintegrant, and then placed into hard or soft capsules. Various diluents, binders, wetting agents, disintegrants, and disintegrants used to prepare tablets of the compound of the present invention can also be used to prepare capsules of the compound of the present invention.

[0029] To prepare the compounds of this invention into injectable formulations, water, ethanol, isopropanol, propylene glycol, or mixtures thereof can be used as solvents, and appropriate amounts of commonly used solubilizers, co-solvents, pH adjusters, and osmotic pressure adjusters can be added. Solubilizers or co-solvents can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin, etc. pH adjusters can be phosphates, acetates, hydrochloric acid, sodium hydroxide, etc.; osmotic pressure adjusters can be sodium chloride, mannitol, glucose, phosphates, acetates, etc. If preparing lyophilized powder injections, mannitol, glucose, etc., can also be added as supporting agents.

[0030] In addition, colorants, preservatives, flavorings, tasters or other additives may be added to pharmaceutical preparations if necessary.

[0031] To achieve the purpose of medication and enhance the therapeutic effect, the drug or drug composition of the present invention can be administered using any known method of administration.

[0032] The dosage of the pharmaceutical compositions of the present invention can vary widely depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration, and the dosage form. Generally, the suitable daily dose range of the compounds of the present invention is 0.001-150 mg / kg body weight, preferably 0.1-100 mg / kg body weight. The above doses can be administered as a single dose unit or divided into several dose units, depending on the physician's clinical experience and the dosing regimen, including the use of other treatment methods.

[0033] The compounds or compositions of the present invention can be taken alone or in combination with other therapeutic or symptomatic drugs. When the compounds of the present invention have a synergistic effect with other therapeutic drugs, their dosage should be adjusted according to the actual situation.

[0034] The compounds of this invention, or their pharmaceutically acceptable salts, can be applied in the pharmaceutical field. In the field of antitumor drugs, for example, in the preparation of anti-gastric cancer drugs, in vivo pharmacodynamic experiments showed that the oral dose of compound STP-2 of this invention had a tumor inhibition rate of 63.68% at 25 mg / kg and 82.66% at 100 mg / kg, demonstrating significant anti-gastric cancer activity. Preliminary oral acute toxicity tests showed that the median lethal dose (LD50) of compound STP-2 of this invention... 50 The LD50 of triptolide is greater than 1 g / kg, while the LD50 of triptolide is greater than 1 g / kg. 50 The concentration was approximately 1 mg / kg. These results indicate that the toxicity of the triptolide derivative STP-2 is significantly lower than that of triptolide, and it exhibits anti-gastric cancer activity at low concentrations. Attached Figure Description

[0035] Figure 1 .Morphology of mouse HGC27 xenograft tumors; Detailed Implementation

[0036] Example 1: Preparation of 18-thiotriptylide (STP-1)

[0037] 500 mg of triptolide (1 equiv) was completely dissolved in 20 ml of toluene, and then 1683 mg of Lawssen's reagent (3 equiv) was added to the flask. The mixture was refluxed at 125 °C with stirring. After 3 h, the reaction was stopped, filtered, and the filtrate was diluted with ethyl acetate. The filtrate was then washed once with a small amount of water and once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered under vacuum. The filtrate was evaporated to dryness to obtain the crude product. Purification was performed by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain a pale yellow solid, which was then prepared by HPLC (IBN-5, isopropanol: n-hexane = 2:1, flow rate: 3 ml / min, t... R (24.2 min) Purification yielded 355.2 mg of pure product, with a yield of 68%. 13 CNMR(101MHz, CDCl3)δ213.5,197.0,157.9,137.7,66.7,65.3,64.6,61.1,60.6,59.1,56.2,40.6,35.4,30.8,26.0,24.1,18.9,18.2,16.5,14.1. 1 H NMR(400MHz,Chloroform-d)δ5.02(dd,J=19.5,2.6Hz,1H),5.00–4.94(m,1H),4.04(dd,J=3.3,2.0 Hz,1H),3.83(d,J=2.9Hz,1H),3.42(d,J=5.4Hz,1H),2.86–2.78(m,1H),2.53–2.44(m,1H),2.40(q ,J=6.9Hz,1H),2.23(dt,J=14.9,5.7Hz,2H),2.10–1.97(m,1H),1.61(dd,J=12.4,5.5Hz,1H),1.30 (ddd,J=18.2,12.0,5.9Hz,1H),1.07(s,3H),0.98(d,J=6.8Hz,3H),0.89(d,J=6.9Hz,3H).HRESIMS m / z=375.1263[M+H] + (calcd for C 20 H 22 O5S,374.1188).

[0038] Example 2: Preparation of 18-thiotriptylide (STP-2) and 18-thiotriptylide (STP-3).

[0039] 50 mg of 18-thiotriptylide (1 equiv) was completely dissolved in 2 ml of methanol, and then 20 mg of NaBH4 (1.2 equiv) was added to the flask. The mixture was stirred at room temperature. After 5 h, the reaction was stopped, filtered, and the filtrate was diluted with ethyl acetate. The filtrate was then washed once with a small amount of water and once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered under vacuum. The filtrate was evaporated to dryness to obtain the crude product. Purification was performed by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain a pale yellow solid. Further purification was performed by HPLC (IB N-5, isopropanol:n-hexane = 95:5, flow rate: 3 ml / min) to obtain pure STP-2 16.1 mg (t) R =18.8min), yield 32%; STP-3 31.3mg(t) R =20.2min), yield 63%.

[0040] STP-2: 13 C NMR (176MHz, CDCl3) δ213.7,158.5,137.6,79.0,73.6,66.4,65.9,60.9,60.2,56.9,54.7,40.5,35.8,30.0,28.3,24.5,18.9,17.9,17.0,13.9.

[0041] 1 H NMR(700MHz,Chloroform-d)δ5.03–4.87(m,2H),3.91(d,J=3.2Hz,1H),3.52(d,J=3.2Hz,1 H),3.42(s,1H),3.38(d,J=5.5Hz,1H),2.73–2.69(m,1H),2.45(d,J=17.1Hz,1H),2.29–2. 16(m,2H),2.02(dd,J=14.7,13.2Hz,1H),1.57(dd,J=12.5,5.5Hz,1H),1.25(s,1H),1.20( dq,J=12.2,6.1Hz,1H),1.12(s,3H),1.01(d,J=6.9Hz,3H),0.88(d,J=6.9Hz,3H).HRESIMS m / z=377.1411[M+H] + (calcd for C 20 H 24 O5S, 376.1344).

[0042] STP-3: 13C NMR (176MHz, CDCl3) δ213.8,159.0,137.6,79.0,66.9,66.1,65.3,62.2,56.2,55.1,52.9,40.6,35.9,30.2,27.8,24.4,19.2,18.9,16.0,13.8.

[0043] 1 H NMR(700MHz,Chloroform-d)δ5.00(dd,J=19.4,2.6Hz,1H),4.98–4.95(m,1H),4.52(s,1H),3.77 (d,J=3.2Hz,1H),3.72(d,J=5.6Hz,1H),3.39(d,J=3.2Hz,1H),2.77–2.70(m,1H),2.47–2.41(m,1 H),2.33(dq,J=14.1,7.0Hz,1H),2.20(dt,J=14.8,5.9Hz,2H),2.02–1.95(m,1H),1.58(dd,J=12. 6,5.6Hz,1H),1.20(td,J=12.4,5.9Hz,1H),1.09(d,J=5.7Hz,6H),0.83(d,J=7.0Hz,3H).HRESIMS m / z=377.1429[M+H] + (calcdfor C 20 H 24 O5S, 376.1344).

[0044] Example 3: Preparation of 18-thio-19-hydroxytriptylide (STP-4)

[0045] 100 mg of 18-thiotriptylide (1 equiv) was completely dissolved in 2 ml of dioxane, and then 117.4 mg of SeO2 (4 equiv) was added to the flask. The mixture was refluxed at 101 °C with stirring. After 3 h, the reaction was stopped, filtered, and the filtrate was diluted with ethyl acetate. The filtrate was then washed once with a small amount of water and once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered under vacuum. The filtrate was evaporated to dryness to obtain the crude product. Purification was performed by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain a pale yellow solid, which was then purified by HPLC preparation (IB N-5, isopropanol: n-hexane = 4:1, flow rate: 3 ml / min) to obtain pure STP-4 91.8 mg (t) R =8.9min), yield 75%. 13C NMR (101MHz, CDCl3) δ223.2,197.3,160.7,137.2,80.4,66.6,65.4,61.0,60.8,59.0,56.0,42.0,35.6,30.0,25.9,23.1,18.5,18.1,16.4,14.3. 1 H NMR(400MHz,Chloroform-d)δ6.15–6.11(m,1H),4.10–3.97(m,2H),3.86–3.72(m,2H),3.45( d,J=5.6Hz,1H),2.91(d,J=13.0Hz,1H),2.72(dt,J=14.7,5.7Hz,1H),2.41(dt,J=13.5,6.8Hz ,2H),2.15(t,J=15.0Hz,1H),2.06–1.95(m,1H),1.56(dd,J=12.2,5.4Hz,1H),1.31–1.18(m, 6H),1.11(d,J=5.5Hz,1H),1.05(s,3H),0.98(d,J=6.6Hz,3H),0.89(d,J=7.0Hz,3H).HRESIMS m / z=391.1208[M+H] + (calcd for C 20 H 22 O6S,390.1137).

[0046] Example 4: Preparation of 18-thio-19-hydroxytriptylide (STP-5) and 18-thio-19-hydroxyepipylide (STP-6)

[0047] The preparation method of Example 2 was followed, and the product was prepared from 18-thio-19-hydroxytriptylide ketone, with a yield of 35% for STP-5 and 40% for STP-6.

[0048] STP-5: 13 C NMR (151MHz, cdcl3) δ196.3,161.4,137.1,80.6,73.5,66.5,65.9,60.8,60.6,56.9,54.7,42.0,36.2,29.4,28.3,23.6,18.6,17.9,17.0,14.2.

[0049] 1H NMR(600MHz,Chloroform-d)δ6.12(d,J=2.5Hz,1H),3.89(d,J=3.2Hz,1H),3.51(d,J=3.1Hz,1H),3.44–3.37(m,2H),3.12(s,1H),2.83–2.77(m,1H),2.71–2.60(m,1H),2.40–2.31(m,1H),2.25(p,J=7.0Hz,1H),2.17–2.12(m,1H),1.99(td,J=14.1,13.4,2.2Hz,1H),1.54–1.48(m,1H),1.15(td,J=11.9,10.0,5.9Hz,1H),1.09(s,3H),1.01(d,J=7.0Hz,3H),0.88(d,J=6.8Hz,3H).HRESIMS m / z=391.1226[M-H] + (calcd forC 20 H 24 O6S,392.1221)。

[0050] STP-6: 13 C NMR(151MHz,cdcl3)δ196.5,161.9,137.0,80.7,67.1,66.3,65.4,62.0,56.1,55.5,53.3,42.0,36.3,29.4,27.8,23.5,19.2,18.7,16.0,14.1.

[0051] 1 H NMR(600MHz,Chloroform-d)δ6.11(d,J=2.6Hz,1H),4.49(s,1H),3.77–3.69(m,2H),3.40(d,J=3.1Hz,1H),2.88–2.81(m,1H),2.67(dt,J=14.8,6.0Hz,1H),2.32(ddt,J=20.7,13.8,6.1Hz,2H),2.16–2.06(m,1H),1.96(dd,J=14.8,13.2Hz,1H),1.50(dd,J=12.3,5.5Hz,1H),1.17(td,J=12.1,5.7Hz,1H),1.14–1.04(m,6H),0.80(d,J=6.9Hz,3H).HRESIMS m / z=391.1223[M-H] + (calcd for C 20 H 24 O6S,392.1221)。

[0052] Pharmacological experiments

[0053] Experiment Example 1: Cytotoxic Activity Test

[0054] 1. Experimental materials: Thiazolium bromide blue tetrazolium (MTT, Sigma, USA), RPMI 1640 medium (Gbico, USA), Dulbecco's modified eagle medium (DMEM, Gbico, USA), Fetal Bovine Serum (FBS, Cbico, USA), Penicillin-Streptomycin (100×) double antibody (Coolaber, China), DMSO (Lambolid, China), HGC27 (human gastric cancer cells), HCT-116 (human colon cancer cells), MCF7 (human breast cancer cells), HepG2 (human liver cancer cells), U251 (human glioma cells), BIOTEK microplate reader.

[0055] 2. Experimental Methods

[0056] (1) Cell culture: HCT116, MCF7, U251 and HepG2 cells were cultured in DMEM medium containing 10% fetal bovine serum, 100 U / mL penicillin and 100 μg / L streptomycin. HGC27 cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum, 100 U / mL penicillin and 100 μg / L streptomycin. Cells were passaged in a 37℃, 5% CO2 saturated humidity incubator. Logarithmic growth cycle cells were selected for the experiment.

[0057] (2) MTT assay: Take cells in the logarithmic growth phase and divide them into 2 × 10⁶ cells per well. 3 Cells were seeded into 96-well plates. The next day, different concentrations (10, 1, and 0.1 μM) of compounds (STP1-STP6 and TPL) were added and incubated for 72 h. At the end of the experiment, MTT solution with a final concentration of 0.5 mg / ml was added to each well, and the cells were incubated at 37°C for another 3 h. Then, the cell supernatant was discarded, and DMSO was added and shaken for 5 minutes to fully dissolve the formazan precipitate. The absorbance (OD) value of the solution was measured at 570 nm using a BIOTEK microplate reader. The effect of the compounds on cell proliferation was calculated using the following formula: Cell proliferation inhibition rate (%) = (OD control - OD compound) / (OD control - OD blank) × 100%. IC50 was calculated using GraphPad Prism 8.0. 50 value.

[0058] 3. Experimental results: as shown in Table 1.

[0059] Table 1 Tumor cytotoxic activity

[0060]

[0061] Example 2: In vivo antitumor efficacy of STP-2 against a human gastric cancer HGC27 xenograft model

[0062] 1. Experimental materials: test compound STP-2; triptolide (TPL, positive control); BALB / c-nu mice, 18-20g, SPF grade, male, provided by Spiford (Beijing) Biotechnology Co., Ltd.

[0063] 2. Experimental methods:

[0064] (1) Procedure: Under aseptic conditions, gastric cancer tumors were dissected from mice and homogenized to prepare a single-cell suspension. The cell count was 5 × 10⁻⁶. 6 / ml. Mix well and inject 0.2ml subcutaneously into the axillary back of each mouse. Wait until the tumor volume reaches 100mm. 3 Animals were randomly divided into groups and administered the drug (day 1). The control group received daily intraperitoneal injections of 0.9% saline, while the drug-treated groups received daily intraperitoneal injections of the corresponding dose of the compound. When the tumors in the control group reached a certain size, the mice were euthanized by cervical dislocation, and the tumor tissue was dissected, weighed, and photographed. Finally, the tumor inhibition rate was calculated to evaluate the intensity of the antitumor effect.

[0065] (2) Grouping: control group, positive drug TPL 0.5mg / kg group (intraperitoneal), STP-2 25mg / kg group (intraperitoneal) and STP-2 100mg / kg group (intraperitoneal).

[0066] (3) Calculation method:

[0067] Tumor inhibition rate (TGI): Inhibition (%) = (CT) / C × 100, where T is the tumor weight in the treatment group and C is the tumor weight in the control group.

[0068] 3. Experimental Results:

[0069] Fifteen days after administration, the tumors of the treated animals were weighed. The effect of compound STP-2 on a human gastric cancer HGC27 xenograft model is described in [link to relevant documentation]. Figure 1 And Table 2.

[0070] Table 2. In vivo antitumor efficacy of compound STP-2 against human gastric cancer HGC27 xenograft model

[0071]

[0072] 1.Data is presented as mean±SD, * P<0.05, **P<0.01, *** P<0.001, **** P < 0.0001 vs. control group; data is analyzed using one-way ANOVA;

[0073] 2. ns: No significant difference.

[0074] Experimental Example 3: Preliminary Acute Toxicity Test of STP-2

[0075] 1. Experimental materials: Test compound STP-2; positive control drug TPL; mouse weighing scale; 1mL sterile syringe; ICR mice, 18-20g, SPF grade, male, provided by Spiford (Beijing) Biotechnology Co., Ltd.

[0076] 2. Experimental methods: Mice were randomly divided into three groups according to their body weight: a control group, an STP-2 (1g / kg) group, and a TPL (2mg / kg) group. After a single intraperitoneal injection of the corresponding dose of the compound, the weight changes and mortality of the mice were recorded for 7 consecutive days. The presence of poisoning symptoms in the treatment groups was also observed, such as lethargy, piloerection, squinting or closing of the eyes, poor activity, sluggish response to external stimuli, and poor appetite.

[0077] 3. Experimental Results: Preliminary acute toxicity tests showed that STP-2 has a low LD50. 50 >1g / kg, while a literature review revealed that the LD50 of triptolide TPL is >1g / kg. 50 The concentration was approximately 1 mg / kg, indicating that the toxicity of compound STP-2 was much lower than that of triptolide. Table 3 shows the survival rate statistics for each group of animals.

[0078] Table 3 Survival rates of animals in each group

[0079]

Claims

1. A compound having the structure of Formula I or a pharmaceutically acceptable salt thereof, R1 is selected from H or OH.

2. Compounds having the structure of Formula II or pharmaceutically acceptable salts thereof, R2 is selected from H or OH; R3 is selected from H or OH; R4 is selected from H or OH.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

4. A pharmaceutical composition comprising, as an active ingredient, any one of the compounds of claims 1-3 or a pharmaceutically acceptable salt thereof, and a pharmacodynamically acceptable carrier or excipient.

5. Use of the compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating tumor diseases.

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