CN106800561A - C20 epimerization salinomycin and its derivative, Preparation Method And The Use - Google Patents

Abstract

The invention belongs to medicinal chemistry art, it is related to C20 epimerization salinomycin and its acylated derivatives and preparation method and anticancer usage, is especially preparing anti-lung cancer, the purposes in colon cancer and liver-cancer medicine.

Description

C20-position epimerization salinomycin and derivatives thereof, preparation method and use thereof

technical field

The invention belongs to the field of medicinal chemistry, and relates to C20-position epimerized salinomycin and its acylated derivatives, a preparation method and an antitumor application, especially an application for treating liver cancer, colon cancer and lung cancer.

Background technique

Cancer stem cells (cancer stem cells, CSCs) are a new potential target for tumor treatment discovered in recent years. Tumor cells with different degrees of differentiation. Existing methods of treating tumors, such as chemotherapy and radiotherapy, mostly target general tumor cells rather than tumor stem cells, which leads to incomplete treatment and still causes drug resistance, recurrence and metastasis of tumors.

Salinomycin (salinomycin) is a polyether ionophore antibiotic isolated from Streptomyces albicans. Salinomycin sodium has been used in poultry as a growth promoter and anticoccidiostat for a long time. Research in 2009 found that salinomycin can highly select breast cancer stem cells in vitro, and can significantly inhibit the growth of breast cancer in mice, and its efficacy is 100 times higher than that of the clinically used anti-tumor drug paclitaxel (Mertins, S.D. Cancer stem cells: a systems biology view of their role in prognosis and therapy. Anti-Cancer Drugs: 2014, 25(4), 353-367.). Salinomycin also has good activity on stem cells in other tumor tissues, such as acute myeloid leukemia stem cells, lung cancer stem cells, gastric cancer stem cells, osteosarcoma stem cells, colorectal cancer stem cells, squamous cell carcinoma stem cells, pancreatic cancer stem cells and prostate cancer stem cells, etc.

In addition, salinomycin also has a great effect on differentiated tumor cells such as leukemia, breast cancer, gastric cancer, colon cancer, pancreatic cancer, esophageal cancer, glioma, liver cancer, bladder cancer, prostate cancer and lung cancer cells. Good inhibitory effect, also has good inhibitory activity to multidrug resistance, radiotherapy resistance and apoptosis resistant cancer cells, such as chronic lymphocytic leukemia and human metastatic breast cancer (Huczynski, A.Salinomycin-A New Cancer Drug Candidate. Chem. Biol. Drug Des., 2012, 79, 235.).

It has been reported in the literature that salinomycin can inhibit P-glycoprotein gp170, interfere with Wnt signaling cascade, increase DNA damage and reduce p21 protein levels, overcome ABC transporter-mediated multidrug resistance and apoptosis tolerance, increase oxidative stress and Increase the level of active oxygen and so on. Among them, salinomycin induces the apoptosis of tumor stem cells by inhibiting the Wnt/β-Catenin signaling pathway, which is considered to be one of the main mechanisms for its anti-tumor activity.

The Wnt/β-Catenin pathway plays an important role in maintaining the characteristics of cancer stem cells, especially the activation of Wnt/β-Catenin can make cancer stem cells acquire resistance to radiotherapy and chemotherapy. Lu et al. found that salinomycin can inhibit the Wnt/β-Catenin signaling pathway in leukemia cells and clarified the mechanism: salinomycin acts on the Wnt/Fzd/LPR complex, and the activity of the LPR (low-density lipoprotein receptor-related protein) complex is inhibited. Salinomycin inhibits Wnt signaling and selectively induces apoptosis in chronic lymphocytic leukemia cells. Proc Natl Acad Sci U SA. 2011; 108(32): 13253-7.).

Subsequently, Tang et al. found that in osteoblastoma cells U2OS, MG63, and SAOS2, salinomycin can reduce the activation phase of GSK3β phosphorylation and accelerate the degradation of β-Catenin, thereby reducing β-Catenin in the nucleus and inhibiting cancer-associated genes. Cyclin D1 expression. King et al. also found that salinomycin induces apoptosis of triple-negative breast cancer tumor cells by inhibiting LPR, thereby inhibiting the Wnt/β-Catenin pathway19. Zhu et al. found that salinomycin can induce the protein level of Wnt receptor LRP in CNE-1, CNE-2 and CNE-2/DDP of nasopharyngeal carcinoma NPC cells, and promote the degradation of β-Catenin. Mao et al. found that activating the wnt1 signaling pathway can significantly accelerate the proliferation of gastric cancer stem cells, and salinomycin played a key role in inhibiting the wnt1 signaling pathway, and then induced the apoptosis of gastric cancer stem cells. Lu et al. recently found that salinomycin can not only inhibit the related Wnt/β-catenin signaling pathway, but also inhibit the mTORC1 signaling pathway by inhibiting the expression of LRP6 in prostate cancer stem cells. The above research results indicate that LRP protein and Wnt/β-catenin pathway are potential important anti-tumor drug targets.

These findings indicate that salinomycin has the potential to be developed as a new type of anticancer drug. So far, preclinical trials of salinomycin in the treatment of triple-negative breast cancer and pediatric high-grade glioma stem cells have been carried out.

However, salinomycin has poor pharmacokinetic properties, poor water solubility, instability under acidic conditions, low bioavailability, and high toxicity to mammals and humans, which brings certain difficulties to its clinical use . The structure-activity relationship research and structure optimization of salinomycin may lead to lead compounds with better activity, lower toxicity and better pharmacokinetic properties.

At present, the research on the medicinal chemistry of salinomycin targeting cancer stem cells has just begun. The reported research is mainly on the modification of C1 and hydroxyl groups. Adam Huczynski’s group synthesized derivatives substituted by esterification or amidation at C1. Antitumor activity was not significantly improved (Antoszczak, M.; Popiel, K.; J.; Wietrzyk, J.; Maj, E.; Janczak, J.; Michalska, G.; Brzezinski, B. , A.Synthesis, cytotoxicity and antibacterial activity of new esters of polyether antibiotic salinomycin, Eur.J.Med.Chem.2014, 76, 435-444); Daniel Strand group synthesized hydroxy acylated derivatives, some of which were found in Compounds with better in vitro activity than salinomycin with 5-fold increased activity (Borgstrom, B.; Huang, XL; Posta, M.; Hegardt, C.; Oredssonb S. and Strand. D. Synthetic modification of salinomycin: selective O -acylation and biological evaluation. Chem. Commun., 2013, 49, 9944.). But in general, the modification strategy is relatively simple, there are not many synthetic derivatives, the activity test research is not in-depth, and the structure-activity relationship is still unclear.

Invention content:

The technical problem solved by the present invention is to provide a class of C20-position epimerized salinomycin and its derivatives and pharmaceutically acceptable salts thereof, their preparation methods, pharmaceutical compositions and their use in the prevention or/and treatment of tumors Applications.

In order to solve the technical problems of the present invention, the present invention provides the following technical solutions:

The first aspect of the technical solution of the present invention is to provide the C20-position epimerized salinomycin represented by the general formula I and its acylated derivatives and pharmaceutically acceptable salts thereof, the specific structure of which is as follows:

Wherein, X is selected from H, Li, Na, K, Ca, Mg, Zn;

R ₁ , R ₂ and R ₃ are independently selected from H, substituted or unsubstituted saturated or unsaturated C ₁ -C ₁₄ alkanoyl, substituted or unsubstituted saturated or unsaturated containing 1-2 heteroatoms C ₁ -C ₁₄ alkyl acyl, substituted or unsubstituted saturated or unsaturated C ₃ -C ₈ cycloalkyl acyl, substituted or unsubstituted saturated or unsaturated C ₃ -C ₈ containing 1-2 heteroatoms Cycloalkylacyl, substituted or unsubstituted C ₆ -C ₁₂ aryl formyl, substituted or unsubstituted C ₅ -C ₁₂ heterocyclyl formyl, the substituents are independently selected from C ₁ -C ₃ alkyl , C ₁ -C ₄ alkoxy, carboxyl, cyano, halogenated C ₁ -C ₃ alkyl, halogen, hydroxyl, nitro, C ₆ -C ₁₂ aryl, C ₆ -C ₁₂ heterocyclyl, all Said heteroatom is selected from N, O, S.

Among the preferred compounds, R ₁ and R ₃ are independently selected from H, R ₂ is selected from H, substituted or unsubstituted saturated or unsaturated C ₁ -C ₆ alkyl acyl, substituted or Unsubstituted saturated or unsaturated C ₁ -C ₆ alkyl acyl, substituted or unsubstituted saturated or unsaturated C ₃ -C ₆ cycloalkyl acyl, substituted or unsubstituted saturated or Unsaturated C ₃ -C ₆ cycloalkylacyl, substituted or unsubstituted C ₆ -C ₁₂ arylformyl, substituted or unsubstituted C ₅ -C ₁₂ heterocyclylformyl, the substituents are independently selected from C ₁ -C ₃ alkyl, C ₁ -C ₄ alkoxy, carboxyl, cyano, halogenated C ₁ -C ₃ alkyl, halogen, hydroxyl, nitro, C ₆ -C ₁₂ aryl, C ₆ - C ₁₂ heterocyclic group, the heteroatom is selected from N, O, S.

Among the more preferred compounds, R ₁ and R ₃ are independently selected from H, R ₂ is selected from H, substituted or unsubstituted saturated or unsaturated C ₁ -C ₄ alkanoyl, substituted with 1-2 heteroatoms Or unsubstituted saturated or unsaturated C ₁ -C ₄ alkyl acyl, substituted or unsubstituted benzoyl, substituted or unsubstituted C ₅ -C ₁₂ heterocyclylformyl, the substituents are independently selected from C ₁ -C ₃ alkyl, C ₁ -C ₄ alkoxy, carboxyl, cyano, halogenated C ₁ -C ₃ alkyl, halogen, hydroxyl, nitro, C ₆ -C ₁₂ aryl, C ₆ -C ₁₂ heterocyclic groups, the heteroatoms are selected from N, O, S.

The heterocyclic group mentioned above is selected from furan, thiophene, pyrrole, thiazole, imidazole, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, tetrahydrothiazole, pyridine, piperidine, and indole.

The most preferred compounds are as follows:

The second aspect of the technical solution of the present invention provides a method for preparing the compound described in the first aspect of the present invention, which includes the following steps:

Wherein, X is selected from H, Li, Na, K, Ca, Mg, Zn;

R ₁ , R ₂ and R ₃ are independently selected from H, substituted or unsubstituted saturated or unsaturated C ₁ -C ₁₄ alkanoyl, substituted or unsubstituted saturated or unsaturated containing 1-2 heteroatoms C ₁ -C ₁₄ alkyl acyl, substituted or unsubstituted saturated or unsaturated C ₃ -C ₈ cycloalkyl acyl, substituted or unsubstituted saturated or unsaturated C ₃ -C ₈ containing 1-2 heteroatoms Cycloalkylacyl, substituted or unsubstituted C ₆ -C ₁₂ aryl formyl, substituted or unsubstituted C ₅ -C ₁₂ heterocyclyl formyl, the substituents are independently selected from C ₁ -C ₃ alkyl , C ₁ -C ₄ alkoxy, carboxyl, cyano, halogenated C ₁ -C ₃ alkyl, halogen, hydroxyl, nitro, C ₆ -C ₁₂ aryl, C ₆ -C ₁₂ heterocyclyl, all Said heteroatom is selected from N, O, S.

Among the preferred compounds, R ₁ and R ₃ are independently selected from H, R ₂ is selected from H, substituted or unsubstituted saturated or unsaturated C ₁ -C ₆ alkyl acyl, substituted or Unsubstituted saturated or unsaturated C ₁ -C ₆ alkyl acyl, substituted or unsubstituted saturated or unsaturated C ₃ -C ₆ cycloalkyl acyl, substituted or unsubstituted saturated or Unsaturated C ₃ -C ₆ cycloalkylacyl, substituted or unsubstituted C ₆ -C ₁₂ arylformyl, substituted or unsubstituted C ₅ -C ₁₂ heterocyclylformyl, the substituents are independently selected from C ₁ -C ₃ alkyl, C ₁ -C ₄ alkoxy, carboxyl, cyano, halogenated C ₁ -C ₃ alkyl, halogen, hydroxyl, nitro, C ₆ -C ₁₂ aryl, C ₆ - C ₁₂ heterocyclic group, the heteroatom is selected from N, O, S.

Among the more preferred compounds, R ₁ and R ₃ are independently selected from H, R ₂ is selected from H, substituted or unsubstituted saturated or unsaturated C ₁ -C ₄ alkanoyl, substituted with 1-2 heteroatoms Or unsubstituted saturated or unsaturated C ₁ -C ₄ alkyl acyl, substituted or unsubstituted benzoyl, substituted or unsubstituted C ₅ -C ₁₂ heterocyclylformyl, the substituents are independently selected from C ₁ -C ₃ alkyl, C ₁ -C ₄ alkoxy, carboxyl, cyano, halogenated C ₁ -C ₃ alkyl, halogen, hydroxyl, nitro, C ₆ -C ₁₂ aryl, C ₆ -C ₁₂ heterocyclic groups, the heteroatoms are selected from N, O, S.

The heterocyclic group mentioned above is selected from furan, thiophene, pyrrole, thiazole, imidazole, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, tetrahydrothiazole, pyridine, piperidine, and indole.

Step 1: Compound a is reacted with trimethylsilyl ethanol to obtain compound b;

Step 2: Compound b obtains compound c by Mitsunobu reaction, wherein the reagents used are diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate and dibenzyl azodicarboxylate One of triphenylphosphine, trimethylphosphine, tributylphosphine and trihexylphosphine and one of p-nitrobenzoic acid, halobenzoic acid and methoxy substituted benzoic acid; The solvents used are alcohol solvents such as tetrahydrofuran, pyridine, dichloromethane, ethyl acetate, acetonitrile, toluene, dimethyl sulfoxide, methanol and ethanol, respectively. Reaction temperature -80°C-200°C;

Step 3: Compound c removes the benzoyl group under the action of a base, wherein the base used is potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium methoxide , sodium ethoxide, hydrazine hydrate, DBU, etc., the solvents used are alcohol solvents such as tetrahydrofuran, pyridine, dichloromethane, ethyl acetate, acetonitrile, toluene, dimethyl sulfoxide, methanol and ethanol, etc.;

Step 4: The compound is reacted with acid anhydride or acid chloride to obtain intermediate d, wherein the acid anhydride used is acetic anhydride, propionic anhydride, butyric anhydride, benzoic anhydride, substituted benzoic anhydride or acetyl chloride, propionyl chloride, butyryl chloride, benzoyl chloride or Substituting benzoyl chloride, etc., the solvents used are alcohol solvents such as tetrahydrofuran, pyridine, dichloromethane, ethyl acetate, acetonitrile, toluene, dimethyl sulfoxide, methanol and ethanol, etc.;

Step 5: Compound e is deesterified under the action of fluorinating reagents, wherein the fluorinating reagents include potassium fluoride, tetrabutylammonium fluoride, silver fluoride, etc., and the solvents used are tetrahydrofuran, pyridine, dichloromethane, Alcohol solvents such as ethyl acetate, acetonitrile, toluene, dimethyl sulfoxide, methanol and ethanol, etc.;

Step 6: The product obtained in step 5 is treated with alkali to obtain the final product, and the alkali is potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium methoxide , sodium ethylate, etc.

The third aspect of the technical solution of the present invention is to provide a pharmaceutical composition, which comprises a therapeutically and/or preventively effective amount of the compound described in the first aspect of the present invention and a pharmaceutically acceptable salt thereof, and optionally a or multiple pharmaceutically acceptable carriers or excipients.

The pharmaceutical composition can be prepared according to methods known in the art. Any dosage form suitable for human or animal use can be prepared by combining the compounds of the present invention with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The content of the compound of the present invention in its pharmaceutical composition is usually 0.1-95% by weight.

The compound of the present invention or the pharmaceutical composition containing it can be administered in the form of a unit dosage, and the route of administration can be enteral or parenteral, such as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and Respiratory tract, skin, vagina, rectum, etc.

The dosage form for administration may be a liquid dosage form, a solid dosage form or a semi-solid dosage form. Liquid dosage forms can be solutions (including true solutions and colloid solutions), emulsions (including o/w type, w/o type and double emulsion), suspensions, injections (including aqueous injections, powder injections and infusion solutions), eye drops Agents, nasal drops, lotions and liniments, etc.; solid dosage forms can be tablets (including ordinary tablets, enteric-coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules ( Including hard capsules, soft capsules, enteric-coated capsules), granules, powders, pellets, dripping pills, suppositories, films, patches, gas (powder) aerosols, sprays, etc.; semi-solid dosage forms can be ointments, Gels, pastes, etc.

The compound of the present invention can be made into common preparations, sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle drug delivery systems.

To prepare the compound of the present invention into tablets, various excipients known in the art can be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, solubilizers. Diluents can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; wetting agents can be water, ethanol, iso Propanol, etc.; binders can be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, arabic mucilage, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hypromellose Base cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; disintegrants can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked poly Vinylpyrrolidone, croscarmellose sodium, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecylsulfonate, etc.; lubricants and co-solvents It can be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol and the like.

Tablets can also be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.

In order to make the administration unit into a capsule, the compound of the present invention as an active ingredient can be mixed with a diluent and a solubilizer, and the mixture can be directly placed in a hard capsule or a soft capsule. The active ingredient compound of the present invention can also be made into granules or pellets with diluents, binders, and disintegrants, and then placed in hard capsules or soft capsules. Various diluents, binders, wetting agents, disintegrants, and solubilizers used in the preparation of tablets of the compound of the present invention can also be used to prepare capsules of the compound of the present invention.

In order to make the compound of the present invention into injection, water, ethanol, isopropanol, propylene glycol or their mixtures can be used as solvent and appropriate amount of solubilizer, cosolvent, pH regulator and osmotic pressure regulator commonly used in this field can be added. The solubilizer or co-solvent can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin, etc.; the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be Sodium chloride, mannitol, glucose, phosphate, acetate, etc. For preparation of freeze-dried powder injection, mannitol, glucose, etc. can also be added as proppants.

In addition, coloring agents, preservatives, fragrances, flavoring agents or other additives can also be added to the pharmaceutical preparations, if necessary.

In order to achieve the purpose of medication and enhance the therapeutic effect, the medicine or pharmaceutical composition of the present invention can be administered by any known administration method.

The dosage of the pharmaceutical composition of the compound of the present invention can vary widely depending on the nature and severity of the disease to be prevented or treated, individual conditions of the patient or animal, administration route and dosage form, etc. In general, a suitable daily dosage range of the compound of the present invention is 0.001-5 mg/Kg body weight. The above-mentioned dosage can be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the doctor and the dosage regimen including the use of other therapeutic means.

The compound or composition of the present invention can be taken alone, or used in combination with other therapeutic drugs or symptomatic drugs. When the compound of the present invention has a synergistic effect with other therapeutic drugs, its dose should be adjusted according to the actual situation.

The fourth aspect of the technical solution of the present invention is to provide the application of the compound described in the first aspect and the pharmaceutical composition described in the third aspect in the preparation of a drug for preventing or/treating tumors.

The tumors mentioned therein include but are not limited to: colon cancer, rectal cancer, pancreatic cancer, gastric cancer, kidney cancer, breast cancer, ovarian cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), prostate cancer, bladder cancer, epithelial cancer Carcinoma, esophageal cancer, cervical cancer, endometrial cancer, adrenocortical carcinoma, basal cell carcinoma, adenocarcinoma, bronchial carcinoma, liver tumor, cholangiocarcinoma, choriocarcinoma, embryonal carcinoma, leukemia, melanoma, glioma, Astrocytoma, medulloblastoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple myeloma, or primary brain tumor. Preferably, the tumor is selected from gastric cancer, lung cancer, breast cancer, colon cancer or liver cancer. More preferably, the tumor is selected from liver cancer, gastric cancer or colon cancer. Particularly preferably, the tumor is selected from liver cancer.

Beneficial technical effect

This study provides a class of salinomycin derivatives with novel structure and strong pharmacological activity, which can be used for the prevention and treatment of cancer and related diseases. All the compounds in the present invention are related to the change of the three-dimensional configuration of salinomycin, and all have novel chemical structures, and most of the salinomycin derivatives in the present invention have strong anti-tumor activity, which is 10 times higher than that of salinomycin Above, the best can reach 50 times, and may be further developed into a new type of anti-tumor drug targeting tumor stem cells.

detailed description

The present invention can be further described by the following examples, however, the scope of the present invention is not limited to the following examples. Those skilled in the art can understand that various changes and modifications can be made in the present invention without departing from the spirit and scope of the present invention. The present invention provides general and/or specific descriptions of the materials and test methods used in the tests. While many of the materials and methods of manipulation which are employed for the purposes of the invention are well known in the art, the invention has been described here in as much detail as possible.

For all of the following examples, standard manipulations and purification methods known to those skilled in the art can be used. All temperatures are in °C (degrees Celsius) unless otherwise indicated. The structures of the compounds were determined by proton nuclear magnetic resonance spectroscopy ( ¹ H NMR) and mass spectroscopy (MS). Proton NMR shifts (δ) are given in parts per million (ppm). The proton nuclear magnetic resonance spectrum was measured with a Mercury-400 nuclear magnetic resonance instrument, deuterated chloroform (CDCl ₃ ) was used as a solvent, and tetramethylsilane (TMS) was used as an internal standard.

Preparation example

The preparation of preparation example 1 salinomycin trimethylsilyl ethyl ester (intermediate 1)

Dissolve 2.4g (3.2mmol) salinomycin in 20ml dichloromethane, add 3ml (20.8mmol) trimethylsilyl ethanol, 1.8ml (10.1mmol) diisopropylethylamine (DIPEA) and 1.0g ( 3.67 mmol) N, N, N', N'-tetramethylchloroformamidine hexafluorophosphate (TCFH), stirred at room temperature for 24 h. Wash with 10ml of 0.1M aqueous HCl solution, 10ml of saturated aqueous sodium bicarbonate solution and 10ml of water respectively, combine the organic phases, dry, concentrate, and separate by column chromatography (eluent petroleum ether:ethyl acetate=3:1) to obtain the target The product was 1.36g, which was a colorless oil, and the yield was 50%. The unreacted salinomycin was recovered.

¹ H NMR (400MHz, CDCl ₃ ) δ6.06 (d, J=10.8Hz, 1H), 5.97 (d, J=10.8Hz, 1H), 4.41 (dtd, J=35.3, 11.2, 5.9Hz, 2H) , 4.09-3.94(m, 3H), 3.93-3.77(m, 2H), 3.68(dd, J=10.4, 7.2Hz, 2H), 3.55(dd, J=10.4, 2.2Hz, 1H), 3.17(td , J=14.7, 7.3Hz, 1H), 3.08-2.91(m, 2H), 2.70(d, J=9.9Hz, 1H), 2.38(dd, J=21.9, 9.4Hz, 2H), 2.27-2.14( m, 1H), 2.12-0.53(m, 55H), 0.07(s, 9H).

Preparation 2 20-epi-20-O-p-nitrobenzoyl salinomycin trimethylsilyl ethyl ester (intermediate 2)

Dissolve 1.0 g of salinomycin trimethylsilyl ethyl ester in 30 ml of tetrahydrofuran, add 3.0 g of triphenylphosphine and 0.5 g of p-nitrobenzoic acid while stirring, then add 2 ml of diisopropyl azodicarboxylate (DIAD ) was slowly added dropwise, stirred at room temperature for 5 h, and TLC detected that the reaction of the raw materials was complete. The solvent was evaporated to dryness and separated by column chromatography (petroleum ether: ethyl acetate = 8:1) to obtain 0.93 g of the target product as a colorless oil with a yield of 80%.

¹ H NMR (400MHz, CDCl ₃ ) δ8.27(d, J=8.2Hz, 2H), 8.16(d, J=8.2Hz, 2H), 6.51(d, J=10.6Hz, 1H), 6.33(dd , J=10.6, 5.3Hz, 1H), 5.22(d, J=5.3Hz, 1H), 4.55-4.32(m, 1H), 4.12-3.99(m, 1H), 3.76(d, J=6.5Hz, 1H), 3.69(d, J=9.6Hz, 1H), 3.59(d, J=10.3Hz, 1H), 3.49(d, J=7.5Hz, 1H), 3.24(dd, J=15.1, 7.7Hz, 1H), 3.01(dd, J=22.0, 11.0Hz, 1H), 2.75(d, J=9.5Hz, 1H), 2.54(s, 1H), 2.13(dd, J=16.0, 9.0Hz, 2H), 1.89(ddd, J=64.8, 25.5, 13.4Hz, 4H), 1.68-0.64(m, 56H), 0.08(s, 9H).

Preparation Example 3 Preparation of 20-epi-salinomycin trimethylsilyl ethyl ester (intermediate 3)

Dissolve 1.0 g of 20-epi-O-p-nitrobenzoyl salinomycin trimethylsilylethyl ester in 20 ml of methanol, add 210 mg of potassium carbonate, stir at room temperature for 30 minutes, and TLC detects that the reaction of the raw materials is complete. Evaporate the solvent to dryness, add 100ml of dichloromethane to dissolve the residue, wash the organic phase with 20ml of 0.1M NaOH aqueous solution and 20ml of water, dry, evaporate the solvent to obtain the crude product of C20-epi-salinomycin trimethylsilyl ethyl ester, pass through the column Chromatographic purification afforded 0.6g.

¹ H NMR (400MHz, CDCl ₃ ) δ6.06 (d, J=10.8Hz, 1H), 5.97 (d, J=10.8Hz, 1H), 4.41 (dtd, J=35.3, 11.2, 5.9Hz, 2H) , 4.09-3.94(m, 3H), 3.93-3.77(m, 2H), 3.68(dd, J=10.4, 7.2Hz, 2H), 3.55(dd, J=10.4, 2.2Hz, 1H), 3.17(td , J=14.7, 7.3Hz, 1H), 3.08-2.91(m, 2H), 2.70(d, J=9.9Hz, 1H), 2.38(dd, J=21.9, 9.4Hz, 2H), 2.27-2.14( m, 1H), 2.12-0.53(m, 55H), 0.07(s, 9H).

The preparation of embodiment 1 20-epi-salinomycin sodium (1)

Dissolve 50 mg of intermediate 3 in DMF, add 50 mg of potassium fluoride, and react overnight at 80° C., and TLC detects that the reaction of the raw materials is complete. The solvent was evaporated to dryness under reduced pressure, the residue was dissolved in ethyl acetate, washed twice with 0.1M Na ₂ CO ₃ aqueous solution, the organic phase was dried, evaporated to dryness to obtain sodium salt, and drained to 30 mg of a colorless foamy solid, yield 62 %.

¹ H NMR (400MHz, CDCl ₃ ) δ6.31(dt, J=21.7, 7.7Hz, 1H), 4.35(d, J=4.5Hz, 1H), 4.26(d, J=10.1Hz, 1H), 4.03 (d, J=2.4Hz, 1H), 3.96(dd, J=10.2, 3.2Hz, 1H), 3.84-3.69(m, 3H), 3.58(d, J=10.1Hz, 1H), 3.43(d, J=11.6Hz, 1H), 2.86(dd, J=10.5, 8.4Hz, 1H), 2.77-2.60(m, 2H), 2.33-0.55(m, 60H).

Example 2 Preparation of 20-epi-20-O-acetyl salinomycin sodium (2)

Dissolve 50 mg of intermediate 3 in 2 ml of pyridine, add 100 μL of acetic anhydride and 5 mg of DMAP, stir at room temperature for 24 hours, TLC detects that the reaction of the raw materials is complete, and then add methanol to quench the reaction. The solvent was evaporated to dryness to obtain a crude product, which was purified by column chromatography, dissolved in DMF, and then added with 50 mg of potassium fluoride, reacted overnight at 80° C., and TLC detected that the reaction of the raw material was complete. The solvent was evaporated to dryness under reduced pressure, the residue was dissolved in ethyl acetate, washed twice with 0.1M Na ₂ CO ₃ aqueous solution, the organic phase was dried, evaporated to dryness to obtain sodium salt, and drained to 30 mg of a colorless foamy solid, yield 62 %.

¹ H NMR (400MHz, CDCl ₃ ) δ8.09-8.06(m, 2H), 7.56(dd, J=10.6, 4.2Hz, 1H), 7.44(t, J=7.7Hz, 2H), 6.09(dd, J=9.9, 6.0Hz, 1H), 5.83(d, J=9.9Hz, 1H), 5.34(d, J=6.0Hz, 1H), 4.64-4.39(m, 1H), 3.85(dd, J=10.6 , 1.8Hz, 1H), 3.74(dt, J=16.7, 8.2Hz, 2H), 3.39(d, J=10.7Hz, 1H), 3.19-2.97(m, 2H), 2.73(ddd, J=9.3, 4.1, 1.9Hz, 1H), 2.68-2.61(m, 1H), 2.20-2.10(m, 1H), 2.34-0.56(m, 65H).

Example 3 Preparation of 20-epi-20-O-propionyl salinomycin sodium (3)

Dissolve 50 mg of intermediate 3 in 2 ml of pyridine, add 100 μL of propionic anhydride and 5 mg of DMAP, stir at room temperature for 24 hours, TLC detects that the reaction of the raw materials is complete, and add methanol to quench the reaction. The solvent was evaporated to dryness to obtain a crude product, which was purified by column chromatography, dissolved in DMF, and then added with 50 mg of potassium fluoride, reacted overnight at 80° C., and TLC detected that the reaction of the raw material was complete. The solvent was evaporated to dryness under reduced pressure, the residue was dissolved in ethyl acetate, washed twice with 0.1M Na ₂ CO ₃ aqueous solution, the organic phase was dried, evaporated to dryness to obtain sodium salt, and drained to 46 mg of a colorless foamy solid, yield 94.5 %.

¹ H NMR (400MHz, CDCl ₃ ) δ6.39 (d, J=10.7Hz, 1H), 6.31 (dd, J=10.6, 5.6Hz, 1H), 5.07 (d, J=5.6Hz, 1H), 4.38 (d, J=6.5Hz, 1H), 4.23 (d, J=10.3Hz, 1H), 3.93 (dd, J=11.0, 4.3Hz, 1H), 3.72 (d, J=9.9Hz, 1H), 3.60 (d, J=9.9Hz, 1H), 3.39(d, J=11.4Hz, 1H), 2.87(td, J=10.9, 3.1Hz, 1H), 2.75-2.60(m, 2H), 2.34-2.24( m, 2H), 2.15-0.58 (m, 65H).

Example 4 Preparation of 20-epi-20-O-isobutyryl salinomycin sodium (4)

Dissolve 50 mg of intermediate 3 in 2 ml of pyridine, add 100 μL of propionic anhydride and 120 ul of triethylamine, stir at room temperature for 24 hours, TLC detects that the reaction of the raw materials is complete, and then add methanol to quench the reaction. The solvent was evaporated to dryness to obtain a crude product, which was purified by column chromatography, dissolved in DMF, and then added with 50 mg of potassium fluoride, reacted overnight at 80° C., and TLC detected that the reaction of the raw material was complete. The solvent was evaporated to dryness under reduced pressure, the residue was dissolved in ethyl acetate, washed twice with 0.1M Na ₂ CO ₃ aqueous solution, the organic phase was dried, evaporated to dryness to obtain sodium salt, and drained to a colorless foamy solid 25 mg, yield 50 %.

¹ H NMR (400MHz, CDCl ₃ ) δ6.41 (d, J=10.7Hz, 1H), 6.31 (dd, J=10.6, 5.7Hz, 1H), 5.07 (d, J=5.7Hz, 1H), 4.40 (q, J=6.6Hz, 1H), 4.25(d, J=10.2Hz, 1H), 3.94(dd, J=11.0, 4.5Hz, 1H), 3.74(dd, J=10.0, 1.5Hz, 1H) , 3.62(d, J=10.1Hz, 1H), 3.40(dd, J=11.8, 1.6Hz, 1H), 2.88(td, J=10.9, 3.1Hz, 1H), 2.70(ddd, J=17.6, 10.6 , 4.8Hz, 2H), 2.50(dt, J=14.0, 7.0Hz, 1H), 2.15-0.63(m, 69H).

Example 5 Preparation of 20-epi-20-O-benzoyl salinomycin sodium (5)

Dissolve 50 mg of intermediate 3 in 2 ml of pyridine, add 100 mg of benzoic anhydride and 5 mg of DMAP, stir at room temperature for 24 hours, TLC detects that the reaction of the raw materials is complete, and then add methanol to quench the reaction. Evaporate the solvent to dryness, dissolve the residue with ethyl acetate, wash with 0.1M NaOH aqueous solution and water respectively, dry and concentrate the organic phase to obtain a crude product, purify it by column chromatography, dissolve it in DMF, and add 50 mg of potassium fluoride, The reaction was carried out at 80° C. overnight, and TLC detected that the reaction of the starting material was complete. The solvent was evaporated to dryness under reduced pressure, the residue was dissolved in ethyl acetate, washed twice with 0.1M Na ₂ CO ₃ aqueous solution, the organic phase was dried, and evaporated to dryness to obtain sodium salt, which was drained into 30 mg of colorless foamy solid, yield 58% .

¹ H NMR (400MHz, CDCl ₃ ) δ7.96(d, J=7.5Hz, 1H), 7.52(t, J=7.1Hz, 1H), 7.39(t, J=7.5Hz, 1H), 6.40(q , J=10.8Hz, 1H), 5.27(d, J=4.8Hz, 1H), 4.38(d, J=6.5Hz, 1H), 4.22(d, J=10.3Hz, 1H), 4.11(dd, J =14.3, 7.1Hz, 1H), 3.91(d, J=8.3Hz, 1H), 3.72(d, J=9.9Hz, 1H), 3.61(d, J=9.8Hz, 1H), 3.37(d, J =11.6Hz, 1H), 2.85(t, J=10.5Hz, 1H), 2.76-2.59(m, 2H), 2.33-0.41(m, 62H).

Example 6 Preparation of 20-epi-20-O-p-fluorobenzoyl salinomycin sodium (6)

Dissolve 50 mg of intermediate 3 in 2 ml of dichloromethane, add 100 μL of p-fluorobenzoyl chloride, 150 μL of triethylamine and 5 mg of DMAP, stir at 50°C for 12 hours, TLC detects that the reaction of the raw materials is complete, and add methanol to quench the reaction. Evaporate the solvent to dryness, dissolve the residue with ethyl acetate, wash with 0.1M NaOH aqueous solution and water respectively, dry and concentrate the organic phase to obtain a crude product, purify it by column chromatography, dissolve it in DMF, and add 50 mg of potassium fluoride, The reaction was carried out at 80° C. overnight, and TLC detected that the reaction of the starting material was complete. The solvent was evaporated to dryness under reduced pressure, the residue was dissolved in ethyl acetate, washed twice with 0.1M Na ₂ CO ₃ aqueous solution, the organic phase was dried, evaporated to dryness to obtain sodium salt, and drained to a colorless foamy solid 40 mg, yield 76 %.

¹ H NMR (400MHz, CDCl ₃ ) δ8.05-7.85(m, 2H), 7.05(t, J=8.5Hz, 2H), 6.38(dt, J=10.6, 8.3Hz, 2H), 5.26(d, J=5.3Hz, 1H), 4.42-4.32(m, 1H), 4.22(d, J=10.3Hz, 1H), 3.90(dd, J=10.6, 2.4Hz, 1H), 3.70(d, J=10.0 Hz, 1H), 3.60(d, J=9.7Hz, 0H), 3.37(d, J=11.6Hz, 1H), 2.85(dd, J=10.5, 9.3Hz, 1H), 2.75-2.53(m, 2H ), 2.28-0.43(m, 62H).

Example 7 Preparation of 20-epi-20-O-p-nitrobenzoyl salinomycin sodium (7)

25 mg of intermediate 2 was dissolved in DMF, and then 25 mg of potassium fluoride was added, and reacted overnight at 80° C., and TLC detected that the reaction of the raw materials was complete. The solvent was evaporated to dryness under reduced pressure, the residue was dissolved in ethyl acetate, washed twice with 0.1M Na ₂ CO ₃ aqueous solution, the organic phase was dried, evaporated to dryness to obtain sodium salt, and drained to a colorless foamy solid 10 mg, yield 40 %.

¹ H NMR (400MHz, CDCl ₃ ) δ8.31(d, J=8.6Hz, 2H), 8.18(d, J=8.7Hz, 2H), 6.50(d, J=10.5Hz, 1H), 6.35(dd , J=10.4, 5.7Hz, 1H), 5.31(d, J=5.7Hz, 1H), 4.22-4.16(m, 1H), 4.06-3.92(m, 2H), 3.86(dd, J=12.4, 5.6 Hz, 1H), 3.78-3.62(m, 3H), 2.99-2.88(m, 1H), 2.80(dd, J=9.3, 7.6Hz, 1H), 2.67(d, J=10.1Hz, 1H), 2.39 -0.44(m, 62H).

Example 8 Preparation of 20-epi-20-O-p-trifluoromethylbenzoyl salinomycin sodium (8)

Dissolve 50 mg of intermediate 3 in 2 ml of dichloromethane, add 100 μL of p-trifluoromethylbenzoyl chloride, 150 μL of triethylamine and 5 mg of DMAP, stir at 50°C for 12 hours, TLC detects that the reaction of the raw materials is complete, and add methanol to quench the reaction. The solvent was evaporated to dryness, and the residue was dissolved in ethyl acetate, washed with 0.1M NaOH aqueous solution and water respectively, and the organic phase was dried and concentrated to obtain a crude product, which was purified by column chromatography. It was dissolved in DMF, and then 50 mg of potassium fluoride was added, and reacted at 80° C. overnight, and TLC detected that the reaction of the raw materials was complete. The solvent was evaporated to dryness under reduced pressure, the residue was dissolved in ethyl acetate, washed twice with 0.1M Na ₂ CO ₃ aqueous solution, the organic phase was dried, evaporated to dryness to obtain sodium salt, and drained to 40 mg of colorless foamy solid, yield 72 %.

¹ H NMR (400MHz, Chloroform-d) δ8.07(d, J=8.1Hz, 2H), 7.67(d, J=8.2Hz, 3H), 6.54-6.29(m, 2H), 5.37(d, J =5.4Hz, 1H), 4.37(d, J=7.1Hz, 1H), 4.22(d, J=10.4Hz, 1H), 3.91(dd, J=11.2, 4.5Hz, 1H), 3.65(dd, J =39.6, 10.1Hz, 2H), 3.39(d, J=11.8Hz, 1H), 2.86(dt, J=11.1, 5.4Hz, 1H), 2.78-2.56(m, 2H), 2.31-0.58(m, 69H).

Example 9 Preparation of 20-epi-20-O-furan-2-formyl salinomycin sodium (9)

Dissolve 50 mg of intermediate 3 in 2 ml of dichloromethane, add 100 μL of furan-2-formyl chloride, 150 μL of triethylamine and 5 mg of DMAP, stir at 50°C for 12 hours, TLC detects that the reaction of the raw materials is complete, and add methanol to quench the reaction. The solvent was evaporated to dryness, the residue was dissolved in ethyl acetate, washed with 0.1M NaOH aqueous solution and water respectively, and the organic phase was dried and concentrated to obtain a crude product. It was dissolved in DMF, and then 50 mg of potassium fluoride was added, and reacted at 80° C. overnight, and TLC detected that the reaction of the raw materials was complete. The solvent was evaporated to dryness under reduced pressure, the residue was dissolved in ethyl acetate, washed twice with 0.1M Na ₂ CO ₃ aqueous solution, the organic phase was dried, evaporated to dryness to obtain sodium salt, and drained to 40 mg of colorless foamy solid, yield 78.5 %.

¹ H NMR (400MHz, Chloroform-d) δ7.59(d, J=1.6Hz, 1H), 7.09(d, J=3.4Hz, 1H), 6.53-6.45(m, 2H), 6.40(t, J =5.9Hz, 1H), 5.33(d, J=5.6Hz, 1H), 4.40(d, J=7.4Hz, 1H), 4.25(d, J=10.4Hz, 1H), 3.95(dd, J=11.5 , 4.5Hz, 1H), 3.77-3.69(m, 1H), 3.63(d, J=11.1Hz, 2H), 3.42(d, J=11.8Hz, 1H), 2.90(td, J=11.0, 3.3Hz , 1H), 2.71(q, J=10.4, 9.4Hz, 2H), 2.26-0.63(m, 67H).

Test case part

Test Example 1 In vitro anti-tumor activity test of 20-position epimerized salinomycin and acylated products

experimental method

(1) Four kinds of tumor cells adherent A549, Bel7402 and HCT-8 in the logarithmic growth phase were selected, digested with trypsin respectively, and prepared a cell suspension of 15000 cells/ml with RPMI1640 culture medium with 10% calf serum , inoculated in a 96-well culture plate, inoculated 190ul per well, cultured at 37°C, 5% CO ₂ for 24h.

(2) In the experimental group, 10ul of samples were added, and the final volume of each well was 200ul, which was supplemented with 1640 culture medium. Culture at 37°C, 5% CO ₂ for 3 days.

(3) Discard the supernatant, add 100 ul of freshly prepared 0.5 mg/ml MTT serum-free culture solution to each well, and continue culturing at 37° C. for 4 h. Discard the supernatant carefully, and add 150ul DMSO to dissolve the MTT formazon precipitate, mix with a micro-ultrasonic oscillator, and measure the optical density value at a wavelength of 570nm on a microplate reader.

(4) Calculate the tumor cell growth inhibition rate.

Result: IC ₅₀ (μM)* of antitumor activity of test compound in vitro

The results showed that the 20-position epimerized salinomycin and the acylated product had significant antitumor activity in vitro. Among them, the pharmacological activities of compounds 3, 4 and 6 were more than 10 times stronger than that of the parent compound salinomycin, and compound 4 had the best pharmacological activity, and its inhibitory effect on liver cancer Bel7402 tumor cells was more than 50 times higher than that of salinomycin.

Claims (9)

1. a class C20 epimerization salinomycin and its derivative and its pharmaceutically acceptable salt, with following structure：

Wherein, X is selected from H, Li, Na, K, Ca, Mg, Zn；

R₁、R₂And R₃Separately it is selected from H, substituted or unsubstituted saturation or unsaturation C₁-C₁₄It is alkyl acyl, miscellaneous containing 1-2 The substitution of atom or unsubstituted saturation or undersaturated C₁-C₁₄Alkyl acyl, substituted or unsubstituted saturation or unsaturation C₃-C₈ Cycloalkanoyl, containing 1-2 heteroatomic substituted or unsubstituted saturations or unsaturation C₃-C₈Cycloalkanoyl, substitution do not take The C in generation₆-C₁₂Aryl formoxyl, substituted or unsubstituted C₅-C₁₂Heterocyclic radical formoxyl, the substitution base is independently selected from C₁-C₃Alkane Base, C₁-C₄Alkoxy, carboxyl, cyano group, halo C₁-C₃Alkyl, halogen, hydroxyl, nitro, C₆-C₁₂Aryl, C₆-C₁₂Heterocyclic radical, institute State hetero atom and be selected from N, O, S.

2. C20 epimerization salinomycin according to claim 1 and its derivative and its pharmaceutically acceptable salt, it is special Levy and be, R₁、R₃It is independent selected from H, R₂Selected from H, substituted or unsubstituted saturation or unsaturation C₁-C₆Alkyl acyl, containing 1-2 Heteroatomic substitution or unsubstituted saturation or undersaturated C₁-C₆Alkyl acyl, substituted or unsubstituted saturation or unsaturation C₃- C₆Cycloalkanoyl, containing 1-2 heteroatomic substituted or unsubstituted saturations or unsaturation C₃-C₆Cycloalkanoyl, substitution or not Substituted C₆-C₁₂Aryl formoxyl, substituted or unsubstituted C₅-C₁₂Heterocyclic radical formoxyl, the substitution base is independently selected from C₁-C₃ Alkyl, C₁-C₄Alkoxy, carboxyl, cyano group, halo C₁-C₃Alkyl, halogen, hydroxyl, nitro, C₆-C₁₂Aryl, C₆-C₁₂Heterocyclic radical, The hetero atom is selected from N, O, S.

3. according to the C20 epimerization salinomycin and its derivative and its pharmaceutically acceptable salt in claim 2, its It is characterised by, R₁、R₃It is independent selected from H, R₂Selected from H, substituted or unsubstituted saturation or unsaturation C₁-C₄Alkyl acyl, containing 1-2 Individual heteroatomic substitution or unsubstituted saturation or undersaturated C₁-C₄Alkyl acyl, substituted or unsubstituted benzoyl, substitution Or unsubstituted C₅-C₁₂Heterocyclic radical formoxyl, the substitution base is independently selected from C₁-C₃Alkyl, C₁-C₄Alkoxy, carboxyl, cyano group, Halo C₁-C₃Alkyl, halogen, hydroxyl, nitro, C₆-C₁₂Aryl, C₆-C₁₂Heterocyclic radical, the hetero atom is selected from N, O, S.

4. C20 epimerization salinomycin and its derivative according to claim any one of 1-3 and its pharmaceutically acceptable Salt, it is characterised in that described heterocyclic radical be selected from furans, thiophene, pyrroles, thiazole, imidazoles, tetrahydrofuran, thiophane, four Hydrogen pyrroles, tetrahydro-thiazoles, pyridine, piperidines, indoles.

5. C20 epimerization salinomycin according to claim 1 and its derivative and its pharmaceutically acceptable salt, it is special Levy and be, the compound is following compounds：

。

6. C20 epimerization salinomycin described in any one of claim 1-5 and its derivative and its pharmaceutically acceptable The preparation method of salt, it is comprised the following steps：

Wherein, X, R₁、R₂And R₃Definition it is identical with claim 1-4；

Step one：Compound a obtains compound b with trimethyl silicon substrate ethanol synthesis；

Step 2：Compound b is reacted by Mitsunobu and obtains compound c, and wherein agents useful for same is selected from azoformic acid diethyl One kind and triphenyl in ester, diisopropyl azodiformate, tert-butyl azodicarboxylate and azoformic acid dibenzyl ester One kind and paranitrobenzoic acid, halogen benzoic acid, methoxy substitution in phosphine, trimethyl-phosphine, tributylphosphine and three hexyl phosphines One kind in benzoic acid；It is sub- that solvent for use is selected from tetrahydrofuran, pyridine, dichloromethane, ethyl acetate, acetonitrile, toluene, dimethyl One kind or any two kinds of combinations in sulfone, methyl alcohol and ethanol.- 200 DEG C of reaction temperature -80 DEG C；

Step 3：Compound c sloughs p-nitrophenyl formoxyl in the presence of alkali, wherein alkali used be selected from potassium carbonate, sodium carbonate, In cesium carbonate, lithium carbonate, lithium hydroxide, NaOH, potassium hydroxide, cesium hydroxide, sodium methoxide, caustic alcohol, hydrazine hydrate, DBU One kind, solvent for use be selected from tetrahydrofuran, pyridine, dichloromethane, ethyl acetate, acetonitrile, toluene, dimethyl sulfoxide (DMSO), methyl alcohol With the one kind in ethanol or any two kinds of combinations；

Step 4：Compound d and acid anhydrides or acyl chloride reaction, obtain intermediate e, wherein acid anhydrides used is selected from acetic anhydride, propionic acid Acid anhydride, butyric anhydride, benzoyl oxide, substituted benzoyl acid anhydrides, acyl chlorides used be selected from chloroacetic chloride, propionyl chloride, butyl chloride, chlorobenzoyl chloride or Substituted benzoyl chloride, it is sub- that solvent for use is selected from tetrahydrofuran, pyridine, dichloromethane, ethyl acetate, acetonitrile, toluene, dimethyl One kind or any two kinds of combinations in sulfone, methyl alcohol and ethanol；

Step 5：Compound e sloughs ester group in the presence of fluorination reagent, and wherein fluorination reagent is selected from potassium fluoride, tetrabutyl fluorine Change ammonium, silver fluoride, solvent for use be selected from tetrahydrofuran, pyridine, dichloromethane, ethyl acetate, acetonitrile, toluene, dimethyl sulfoxide (DMSO), One kind or any two kinds of combinations in methyl alcohol and ethanol；

Step 6：The product that step 5 is obtained uses alkali process again, obtains end-product, alkali be selected from potassium carbonate, sodium carbonate, cesium carbonate, Lithium carbonate, lithium hydroxide, NaOH, potassium hydroxide, cesium hydroxide, sodium methoxide, caustic alcohol.

7. a kind of pharmaceutical composition, it is characterised in that comprising C20 epimerization salt described in claim any one of 1-5 Mycin and its derivative and its pharmaceutically acceptable salt and one or more optional pharmaceutically acceptable carrier or tax Shape agent.

8. C20 epimerization salinomycin described in any one of claim 1-5 and its derivative and its pharmaceutically acceptable The application of pharmaceutical composition described in salt and claim 7 in terms of prevention or/and tumor is prepared.

9. application according to claim 8, it is characterised in that described tumour include leukaemia, breast cancer, stomach cancer, colon cancer, Cancer of pancreas, cancer of the esophagus, glioma, liver cancer, carcinoma of urinary bladder, prostate cancer and lung cancer.