CN106800561A - C20 epimerization salinomycin and its derivative, Preparation Method And The Use - Google Patents
C20 epimerization salinomycin and its derivative, Preparation Method And The Use Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
- C07D493/20—Spiro-condensed systems
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
Technical field
The invention belongs to medicinal chemistry art, it is related to C20 epimerization salinomycin and its acylated derivatives and system
Preparation Method and anticancer usage, in particular for treatment liver cancer, the purposes of colon cancer and lung cancer.
Background technology
Tumor stem cell (cancer stem cell, CSC) is a new potential treatment tumour of discovered in recent years
Target spot, they are the cell colonys that the sub-fraction being present in tumor tissues has stem cell properties, with self-renewing
Ability, can form the tumour cell of different differentiation degrees.The method such as chemotherapy and radioactivity of existing treatment tumour are controlled
Treat is directed to general tumour cell, rather than tumor stem cell, this results in treatment not thoroughly, can still cause tumour resistance,
Recurrence and transfer.
Salinomycin (salinomycin) is that isolated a kind of many polyethers ionophore types from streptomyces albus resist
Raw element, all the time, Salinomycin Sodium is used for poultry as growth promoter and anticoccidiosis medicine.The research of 2009 finds that salt is mould
Element in vitro can high selectivity breast carcinoma stem cell, the growth of breast cancer can be substantially suppressed in Mice Body, its effect ratio faces
Antitumor drug paclitaxel (Mertins, S.D.Cancer the stem cells high 100 times used on bed：a systems
biology view of their role in prognosis and therapy.Anti-Cancer Drugs：2014,25
(4), 353-367.).Salinomycin also has good activity, such as acute myelogenous leukemia to the stem cell in other tumor tissues
Stem cell, lung cancer stem cell, stomach cancer stem cell, osteosarcoma stem cell, large intestine cancer stem cell, squamous cell cancer stem cell, pancreas
Cancer stem cell and prostate cancer stem cells etc..
In addition, salinomycin also to break up tumour cell for example 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 tumor cell etc. have good inhibiting effect, also right
The cancer cell of MDR, radiotherapy tolerance and Apoptosis tolerance has good inhibitory activity, and such as chronic lymphocytic is white
Blood disease and mankind's metastatic breast cancer (Huczynski, A.Salinomycin-A New Cancer Drug
Candidate.Chem.Biol.Drug Des., 2012,79,235.).
Document report salinomycin has suppression P- glycoprotein gp170, interference Wnt signal cascades, increases DNA damage and reduction
P21 protein levels, overcome the protein mediated MDR of abc transport and apoptosis to tolerate, increase oxidative stress and improve activity
Oxygen level etc. is acted on.Wherein salinomycin is by suppressing Wnt/ β-Catenin signal paths so as to induced tumor stem cell apoptosis quilt
It is considered one of its dominant mechanism for playing antitumor activity.
Wnt/ β-Catenin paths are maintaining cancer stem cell characteristic to play an important role, especially Wnt/ β-Catenin activation
Cancer stem cell can be made to obtain radiotherapy and chemoresistant.Lu etc. find salinomycin can suppress leukaemia Wnt/ β-
Catenin signal paths simultaneously illustrate mechanism：Salinomycin acts on Wnt/Fzd/LPR complexs, LPR (low-density lipoprotein receptors
Body associated protein) complex activity inhibited, so as to cause downstream Wnt target gene LEF1, Cyclin D1 and
Fibronectin expression is lowered, and final result is cancer cell-apoptosis (Lu D, Choi MY, Yu J, Castro JE, Kipps
TJ, Carson DA.Salinomycin inhibits Wnt signaling and selectively induces
apoptosis in chronic lymphocytic leukemia cells.Proc Natl Acad Sci U S
A.2011；108(32)：13253-7.).
Then, Tang etc. has found osteoblast oncocyte U2OS, MG63 and SAOS2 again in, salinomycin can reduce GSK3 β phosphorus
Acidifying level activation phase activity, accelerated degradation β-Catenin, so that β-Catenin are reduced in core, suppress cancer associated gene
Cyclin D1 are expressed.King etc. it has also been found that salinomycin is by suppressing LPR, and then suppresses Wnt/ β-Catenin paths, so as to lure
Lead triple negative breast cancer apoptosis of tumor cells 19.Zhu etc. find inducible nasopharyngeal carcinoma NPC cells CNE-1, the CNE-2 of salinomycin and
Wnt acceptors LRP protein levels in CNE-2/DDP, and promote β-Catenin to degrade.Mao etc. has found the activation signal paths of wnt 1
The propagation of gastric cancer tumor stem cell can substantially be accelerated, and salinomycin has played key effect in the signal paths of wnt 1 are suppressed,
Then the tune of induction gastric cancer tumor stem cell is died.Lu etc. has found salinomycin in tumor of prostate stem cell by suppressing recently
The expression of LRP6, can not only suppress related Wnt/ β-catenin signal paths, can also suppress mTORC1 signal paths.More than
Result of study illustrates that LRP albumen and Wnt/ β-catenin paths are potential important antineoplastic target spots.
These results of study show that it is a kind of potential of new cancer therapy drug that salinomycin has research and development.Up to the present,
Salinomycin treatment triple negative breast cancer, the preclinical test of children High Grade Gliomas stem cell are carried out.
However, salinomycin pharmacokinetic property is not good enough, water-soluble very poor, unstable under acid condition, bioavailability
Low and larger to mammal and people's toxicity, this brings certain difficulty to its Clinical practice.And structure is carried out to salinomycin
The research of effect relation and structure optimization, it is possible to obtain it is active more preferably, toxicity is lower and pharmacokinetic property preferably first
Lead compound.
At present, the salinomycin pharmaceutical chemistry research for being directed to tumor stem cell target spot has just just started, the research reported
It is main in the modification of C1 and hydroxyl, Adam Huczynski are small to be combined into that C1 is bit esterified or derivative of amidatioon substitution
Thing, anti tumor activity in vitro is not significantly increased (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
E salinomycin, Eur.J.Med.Chem.2014,76,435-444)；Daniel Strand are small to be combined into acylated hydroxy
Derivative, wherein be found that some in vitro than salinomycin activity preferably compounds, activity improve 5 times (Borgstrom,
B.；Huang, X.L.；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 generally speaking, modify tactful fairly simple, the derivative of synthesis
Thing is few, and active testing is studied not deeply, and structure-activity relationship is not clear.
The content of the invention：
Present invention solves the technical problem that being to provide a class C20 epimerization salinomycin and its derivative and its pharmacy
Upper acceptable salt, its preparation method, pharmaceutical composition and its application in terms of preventing or/and treating tumour.
To solve technical problem of the invention, the present invention provides following technical scheme：
The first aspect of technical solution of the present invention there is provided C20 epimerization salinomycin shown in formula I and its
Acylated derivatives and its pharmaceutically acceptable salt, concrete structure are as follows：
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-C14Alkyl acyl, containing 1-2
Individual heteroatomic substitution or unsubstituted saturation or undersaturated C1-C14Alkyl acyl, substituted or unsubstituted saturation or unsaturation
C3-C8Cycloalkanoyl, containing 1-2 heteroatomic substituted or unsubstituted saturations or unsaturation C3-C8Cycloalkanoyl, substitution
Or unsubstituted C6-C12Aryl formoxyl, substituted 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-C12It is miscellaneous
Ring group, the hetero atom is selected from N, O, S.
Wherein preferred compound, R1、R3It is independent selected from H, R2Selected from H, substituted or unsubstituted saturation or unsaturation
C1-C6Alkyl acyl, containing the heteroatomic substitutions of 1-2 or unsubstituted saturation or undersaturated C1-C6Alkyl acyl, substitution or not
Substituted saturation or unsaturation C3-C6Cycloalkanoyl, containing 1-2 heteroatomic substituted or unsubstituted saturations or unsaturation C3-
C6Cycloalkanoyl, substituted or unsubstituted C6-C12Aryl formoxyl, substituted or unsubstituted C5-C12Heterocyclic radical formoxyl, institute
State substitution base and be 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.
Wherein preferred compound, R1、R3It is independent selected from H, R2Selected from H, substituted or unsubstituted saturation or unsaturation
C1-C4Alkyl acyl, containing the heteroatomic substitutions of 1-2 or unsubstituted saturation or undersaturated C1-C4Alkyl acyl, substitution or not
Substituted benzoyl, substituted 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 miscellaneous original
Son is selected from N, O, S.
Above-described heterocyclic radical is selected from furans, thiophene, pyrroles, thiazole, imidazoles, tetrahydrofuran, thiophane, tetrahydrochysene pyrrole
Cough up, tetrahydro-thiazoles, pyridine, piperidines, indoles.
Most preferred compound is as follows：
The second aspect of technical solution of the present invention provides the method for preparing compound described in first aspect present invention, its bag
Include following steps：
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-C14Alkyl acyl, containing 1-2
Individual heteroatomic substitution or unsubstituted saturation or undersaturated C1-C14Alkyl acyl, substituted or unsubstituted saturation or unsaturation
C3-C8Cycloalkanoyl, containing 1-2 heteroatomic substituted or unsubstituted saturations or unsaturation C3-C8Cycloalkanoyl, substitution
Or unsubstituted C6-C12Aryl formoxyl, substituted 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-C12It is miscellaneous
Ring group, the hetero atom is selected from N, O, S.
Wherein preferred compound, R1、R3It is independent selected from H, R2Selected from H, substituted or unsubstituted saturation or unsaturation
C1-C6Alkyl acyl, containing the heteroatomic substitutions of 1-2 or unsubstituted saturation or undersaturated C1-C6Alkyl acyl, substitution or not
Substituted saturation or unsaturation C3-C6Cycloalkanoyl, containing 1-2 heteroatomic substituted or unsubstituted saturations or unsaturation C3-
C6Cycloalkanoyl, substituted or unsubstituted C6-C12Aryl formoxyl, substituted or unsubstituted C5-C12Heterocyclic radical formoxyl, institute
State substitution base and be 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.
Wherein preferred compound, R1、R3It is independent selected from H, R2Selected from H, substituted or unsubstituted saturation or unsaturation
C1-C4Alkyl acyl, containing the heteroatomic substitutions of 1-2 or unsubstituted saturation or undersaturated C1-C4Alkyl acyl, substitution or not
Substituted benzoyl, substituted 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 miscellaneous original
Son is selected from N, O, S.
Above-described heterocyclic radical is selected from furans, thiophene, pyrroles, thiazole, imidazoles, tetrahydrofuran, thiophane, tetrahydrochysene pyrrole
Cough up, tetrahydro-thiazoles, pyridine, piperidines, indoles.
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 respectively azo diformazan
One kind in diethyl phthalate, diisopropyl azodiformate, tert-butyl azodicarboxylate and azoformic acid dibenzyl ester and
One kind and paranitrobenzoic acid, halogen benzoic acid, methoxy in triphenylphosphine, trimethyl-phosphine, tributylphosphine and three hexyl phosphines
One kind in base substituted benzoic acid；Solvent for use be respectively tetrahydrofuran, pyridine, dichloromethane, ethyl acetate, acetonitrile, toluene,
Alcohols solvents such as dimethyl sulfoxide (DMSO), methyl alcohol and ethanol etc..- 200 DEG C of reaction temperature -80 DEG C；
Step 3：Compound c sloughs benzoyl in the presence of alkali, wherein alkali used is potassium carbonate, sodium carbonate, carbonic acid
Caesium, lithium carbonate, lithium hydroxide, NaOH, potassium hydroxide, cesium hydroxide, sodium methoxide, caustic alcohol, hydrazine hydrate, DBU etc., it is used
Solvent is respectively the alcohol such as tetrahydrofuran, pyridine, dichloromethane, ethyl acetate, acetonitrile, toluene, dimethyl sulfoxide (DMSO), methyl alcohol and ethanol
Class solvent etc.；
Step 4：Compound and acid anhydrides or acyl chloride reaction, obtain intermediate d, wherein acid anhydrides used is acetic anhydride, propionic acid
Acid anhydride, butyric anhydride, benzoyl oxide, substituted benzoyl acid anhydrides or chloroacetic chloride, propionyl chloride, butyl chloride, chlorobenzoyl chloride or substituted benzoyl
Acyl chlorides etc., solvent for use is respectively tetrahydrofuran, pyridine, dichloromethane, ethyl acetate, acetonitrile, toluene, dimethyl sulfoxide (DMSO), first
Alcohols solvent such as alcohol and ethanol etc.；
Step 5：Compound e sloughs ester group in the presence of fluorination reagent, and wherein fluorination reagent includes potassium fluoride, four fourths
Base ammonium fluoride, silver fluoride etc., solvent for use are respectively tetrahydrofuran, pyridine, dichloromethane, ethyl acetate, acetonitrile, toluene, two
Alcohols solvents such as methyl sulfoxide, methyl alcohol and ethanol etc.；
Step 6：The product that step 5 is obtained uses alkali process again, obtains end-product, and alkali is respectively potassium carbonate, sodium carbonate, carbon
Sour caesium, lithium carbonate, lithium hydroxide, NaOH, potassium hydroxide, cesium hydroxide, sodium methoxide, caustic alcohol etc..
The third aspect of technical solution of the present invention there is provided a kind of pharmaceutical composition, and it includes treatment and/or prevention has
Compound and its pharmaceutically acceptable salt described in the first aspect present invention of effect amount, and one or more optional pharmacy can
The carrier or excipient of receiving.
The pharmaceutical composition can be prepared according to method well known in the art.Can by by the compounds of this invention with it is a kind of or many
Plant pharmaceutically acceptable solid or liquid excipient and/or assistant agent is combined, be made and be suitable to any formulation that human or animal uses.
Content of the compounds of this invention in its pharmaceutical composition is usually 0.1-95 weight %.
The compounds of this invention or the pharmaceutical composition containing it can be administered in a unit, and method of administration can be enteron aisle
Or non-bowel, such as oral, intravenous injection, intramuscular injection, hypodermic injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin,
Vagina, rectum etc..
Form of administration can be liquid dosage form, solid dosage forms or semisolid dosage form.Liquid dosage form can be solution (including
True solution and colloidal solution), emulsion (including o/w types, w/o types and emulsion), supensoid agent, injection (including liquid drugs injection, powder-injection
And transfusion), eye drops, nasal drop, lotion and liniment etc.；Solid dosage forms can be tablet (including ordinary tablet, enteric coatel tablets, lozenge,
Dispersible tablet, chewable tablets, effervescent tablet, oral disnitegration tablet), capsule (including hard shell capsules, soft capsule, capsulae enterosolubilis), granule, dissipate
Agent, micropill, dripping pill, suppository, film, paster, the agent of gas (powder) mist, spray etc.；Semisolid dosage form can be ointment, gel
Agent, paste etc..
It is sustained release preparation, controlled release preparation, targeting preparation and various that the compounds of this invention can be made ordinary preparation, also be made
Particulate delivery system.
In order to the compounds of this invention is made into tablet, various excipient well known in the art can be widely used, including it is dilute
Release agent, binder, wetting agent, disintegrant, lubricant, cosolvent.Diluent can be starch, dextrin, sucrose, glucose, breast
Sugar, mannitol, sorbierite, xylitol, microcrystalline cellulose, calcium sulfate, calcium monohydrogen phosphate, calcium carbonate etc.；Wetting agent can be water, second
Alcohol, isopropanol etc.；Adhesive can be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, Arabic gum
Slurry, gelatine size, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, card
Ripple nurse, polyvinylpyrrolidone, polyethylene glycol etc.；Disintegrant can be dried starch, microcrystalline cellulose, low substituted hydroxy-propyl fiber
Element, PVPP, Ac-Di-Sol, sodium carboxymethyl starch, sodium acid carbonate and citric acid, polyoxy second
Alkene sorbitan fatty acid ester, dodecyl sodium sulfate etc.；Lubricant and cosolvent can be talcum powder, silica, tristearin
Hydrochlorate, tartaric acid, atoleine, polyethylene glycol etc..
Tablet can also be further made coating tablet, such as sugar coated tablet, thin membrane coated tablet, ECT, or it is double
Synusia and multilayer tablet.
In order to administration unit is made into capsule, active ingredient the compounds of this invention can be mixed with diluent, cosolvent
Close, during mixture is placed directly within into hard shell capsules or soft capsule.Also can be by active ingredient the compounds of this invention elder generation and diluent, bonding
Agent, disintegrant are made particle or micropill, then are placed in hard shell capsules or soft capsule.For preparing each dilute of the compounds of this invention tablet
Release the capsule that agent, binder, wetting agent, disintegrant, cosolvent kind can also be used for preparing the compounds of this invention.
It is that the compounds of this invention is made injection, water, ethanol, isopropanol, propane diols or their mixture can be used
Make solvent and add appropriate solubilizer, cosolvent, pH adjusting agent, osmotic pressure regulator commonly used in the art.Solubilizer or hydrotropy
Agent can be poloxamer, lecithin, HP-β-CD etc.；PH adjusting agent can be phosphate, acetate, hydrochloric acid, hydrogen
Sodium oxide molybdena etc.；Osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate etc..Such as prepare freeze-dried powder
Injection, can also add mannitol, glucose etc. as proppant.
Additionally, if desired, can also be to addition colouring agent, preservative, spices, flavouring or other additions in pharmaceutical preparation
Agent.
To reach medication purpose, strengthen therapeutic effect, medicine of the invention or pharmaceutical composition known can be given with any
Prescription method is administered.
The dosage of the compounds of this invention pharmaceutical composition is according to the property to be prevented or treated disease and serious journey
The individual instances of degree, patient or animal, method of administration and formulation etc. can have change on a large scale.In general, the present inventionization
The daily Suitable dosage ranges of compound are 0.001-5mg/Kg body weight.Above-mentioned dosage with a dosage unit or can be divided into several
Dosage unit administration, this depends on the clinical experience of doctor and including the dosage regimen with other treatment means.
Compound of the invention or composition can individually be taken, or merge with other treatment medicine or symptomatic drugs and use.
When compound of the invention and other medicines have synergy, its dosage should be adjusted according to actual conditions.
The fourth aspect of technical solution of the present invention is to provide medicine described in compound described in first aspect and the third aspect
Application of the composition in prevention or/tumor is prepared.
Wherein described tumour is included but is not limited to：Colon and rectum carcinoma, cancer of pancreas, stomach cancer, kidney, breast cancer, ovary
Cancer, lung cancer (including ED-SCLC and non-small cell lung cancer), prostate cancer, carcinoma of urinary bladder, epithelioma, the cancer of the esophagus, cervical carcinoma, son
Endometrial carcinoma, adrenocortical carcinoma, basal-cell carcinoma, gland cancer, bronchiolar carcinoma, hepatoma, cholangiocarcinoma, choriocarcinoma, embryonal carcinoma, white blood
Disease, melanoma, glioma, astrocytoma, medulloblastoma, hodgkin's lymphomas, non-hodgkin's drench
Bar knurl, Huppert's disease or primary brain tumor.Preferably, the tumour is selected from stomach cancer, lung cancer, breast cancer, colon cancer or liver
Cancer.It is furthermore preferred that the tumour is selected from liver cancer, stomach cancer or colon cancer.Particularly preferred, the tumour is selected from liver cancer.
Advantageous Effects
This research contents provides the salinomycin derivative that a class formation is novel, pharmacological activity is stronger, can be used for cancer and
The prevention and treatment of its associated conditions.All compounds are related to the change of salinomycin spatial configuration in the present invention, are respectively provided with new
The chemical constitution of grain husk, and most of salinomycin derivative has very strong antitumor activity in the present invention, is improve than salinomycin
More than 10 times, best can reach 50 times, may further research and develop as novel targeted tumor stem cell antineoplastic.
Specific embodiment
The present invention can be conducted further description by the following examples, however, the scope of the present invention is not limited
In following embodiments.One of skill in the art, can be with it is understood that on the premise of without departing substantially from the spirit and scope of the present invention
Various change and modification are carried out to the present invention.The present invention to used in experiment to material and test method carry out generality
And/or specific description.Although for realize many materials that the object of the invention used and operating method be it is known in the art that
But the present invention is still described in detail as far as possible herein.
For following whole embodiments, it is possible to use standard operation well known by persons skilled in the art and purification process.Remove
Non- to be otherwise noted, all temperature are represented with DEG C (degree Celsius).The structure of compound be by proton nmr spectra (1H NMR) and
Mass spectrum (MS) is come what is determined.Hydrogen nuclear magnetic resonance spectral displacement (δ) is given with the unit of hundred a ten thousandths (ppm).Proton nmr spectra
With Mercury-400 type nmr determinations, deuterochloroform (CDCl3) make solvent, tetramethylsilane (TMS) is internal standard.
Preparation example
The preparation of salinomycin trimethyl silicon substrate ethyl ester (intermediate 1) of preparation example 1
2.4g (3.2mmol) salinomycin is dissolved in 20ml dichloromethane, 3ml (20.8mmol) trimethyl silicon substrate second is added
Alcohol, 1.8ml (10.1mmol) diisopropylethylamine (DIPEA) and 1.0g (3.67mmol) N, N, N ', N '-tetramethyl chloromethane amidine six
Fluorophosphate (TCFH), stirs 24h at room temperature.0.1M HCl/waters solution 10ml, saturated sodium bicarbonate aqueous solution 10ml are used respectively
Washed with water 10ml, merge organic phase, dried, concentration, by column chromatography for separation, (eluent petroleum ether: ethyl acetate=3: 1), obtains
It is colorless oil to target product 1.36g, yield 50% reclaims unreacted salinomycin.
1H NMR (400MHz, CDCl3) δ 6.06 (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)
20-epi-20-O- p-nitrophenyls formoxyl salinomycin trimethyl silicon substrate ethyl ester (intermediate 2) of preparation example 2
1.0g salinomycin trimethyl silicon substrate ethyl esters are dissolved in 30ml tetrahydrofurans, in stirring add 3.0g triphenylphosphines and
, then be slowly dropped into for 2ml diisopropyl azodiformates (DIAD) by 0.5g paranitrobenzoic acids, and 5h, TLC inspections are stirred at room temperature
Survey raw material reaction complete.Solvent evaporated, by column chromatography for separation (petroleum ether: ethyl acetate=8: 1), obtain target product 0.93g,
It is colorless oil, yield 80%.
1H NMR (400MHz, CDCl3) δ 8.27 (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)
The preparation (intermediate 3) of the 20-epi- salinomycin trimethyl silicon substrate ethyl esters of preparation example 3
1.0g 20-epi-O- p-nitrophenyl formoxyl salinomycin trimethyl silicon substrate ethyl esters are dissolved in 20ml methyl alcohol, are added
210mg potassium carbonate, is stirred at room temperature 30 minutes, and TLC detection raw material reactions are complete.Solvent evaporated, adds the dissolving of 100ml dichloromethane residual
Thing is stayed, organic phase is washed with the 20ml 0.1M NaOH aqueous solution, 20ml, dried again, and solvent evaporated obtains C20-epi- salinomycins
Trimethyl silicon substrate ethyl ester, 0.6g is obtained by column chromatography purifying.
1H NMR (400MHz, CDCl3) δ 6.06 (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 (1) of the 20-epi- Salinomycin Sodiums of embodiment 1
50mg intermediates 3 are dissolved in DMF, 50mg potassium fluorides are added, overnight, TLC detects raw material reaction for 80 DEG C of reactions
Completely.Evaporated under reduced pressure solvent, residue with Ethyl acetate dissolving, uses 0.1M Na2CO3The aqueous solution is washed twice, and organic phase is dried,
It is evaporated and obtains sodium salt, drains into colorless foamy solid 30mg, yield 62%.
1H NMR (400MHz, CDCl3) δ 6.31 (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)
The preparation (2) of the 20-epi-20-O- acetyl group Salinomycin Sodiums of embodiment 2
50mg intermediates 3 are dissolved in 2ml pyridines, 100 μ L acetic anhydrides and 5mg DMAP is added, when stirring 24 at room temperature,
TLC detection raw material reactions are complete, add methyl alcohol that reaction is quenched.Solvent evaporated obtains crude product, is purified by column chromatography, is dissolved in
In DMF, 50mg potassium fluorides are added, overnight, TLC detection raw material reactions are complete for 80 DEG C of reactions.Evaporated under reduced pressure solvent, residue is used
Ethyl acetate dissolves, and uses 0.1M Na2CO3The aqueous solution is washed twice, and organic phase is dried, and is evaporated and is obtained sodium salt, drains into colourless bubble
Foam shape solid 30mg, yield 62%.
1H NMR (400MHz, CDCl3) δ 8.09-8.06 (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)
The preparation (3) of the 20-epi-20-O- propiono Salinomycin Sodiums of embodiment 3
50mg intermediates 3 are dissolved in 2ml pyridines, 100 μ L propionic andydrides and 5mg DMAP is added, when stirring 24 at room temperature,
TLC detections raw material reaction completely, adds methyl alcohol that reaction is quenched.Solvent evaporated obtains crude product, is purified by column chromatography, is dissolved in
In DMF, 50mg potassium fluorides are added, overnight, TLC detection raw material reactions are complete for 80 DEG C of reactions.Evaporated under reduced pressure solvent, residue is used
Ethyl acetate dissolves, and uses 0.1M Na2CO3The aqueous solution is washed twice, and organic phase is dried, and is evaporated and is obtained sodium salt, drains into colourless bubble
Foam shape solid 46mg, yield 94.5%.
1H NMR (400MHz, CDCl3) δ 6.39 (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)
The preparation (4) of the 20-epi-20-O- isobutyryl Salinomycin Sodiums of embodiment 4
50mg intermediates 3 are dissolved in 2ml pyridines, 100 μ L propionic andydrides and 120ul triethylamines is added, 24 are stirred at room temperature
When, TLC detection raw material reactions are complete, add methyl alcohol that reaction is quenched.Solvent evaporated obtains crude product, is purified by column chromatography, and its is molten
In DMF, 50mg potassium fluorides are added, overnight, TLC detection raw material reactions are complete for 80 DEG C of reactions.Evaporated under reduced pressure solvent, residue
Dissolved with ethyl acetate, use 0.1M Na2CO3The aqueous solution is washed twice, and organic phase is dried, and is evaporated and is obtained sodium salt, is drained into colourless
Foaming solid 25mg, yield 50%.
1H NMR (400MHz, CDCl3) δ 6.41 (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)
The preparation (5) of the 20-epi-20-O- benzoyl Salinomycin Sodiums of embodiment 5
50mg intermediates 3 are dissolved in 2ml pyridines, 100mg benzoyl oxides and 5mg DMAP is added, 24 are stirred at room temperature
When, TLC detection raw material reactions are complete, add methyl alcohol that reaction is quenched.Solvent evaporated, uses ethyl acetate dissolution residual substance, then use respectively
The 0.1M NaOH aqueous solution, washing, organic phase are dried and are concentrated to give crude product, are purified by column chromatography, are dissolved in DMF, then
50mg potassium fluorides are added, overnight, TLC detection raw material reactions are complete for 80 DEG C of reactions.Evaporated under reduced pressure solvent, residue with Ethyl acetate
Dissolving, uses 0.1MNa2CO3The aqueous solution is washed twice, and organic phase is dried, and is evaporated and is obtained sodium salt, drains into colorless foamy solid
30mg, yield 58%.
1H NMR (400MHz, CDCl3) δ 7.96 (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)
Preparations (6) of the 20-epi-20-O- of embodiment 6 to fluoro benzoyl Salinomycin Sodium
50mg intermediates 3 are dissolved in 2ml dichloromethane, 100 μ L is added to fluorobenzoyl chloride, 150 μ L triethylamines and 5mg
DMAP, during 50 DEG C of stirrings 12, TLC detection raw material reactions are complete, add methyl alcohol that reaction is quenched.Solvent evaporated, is dissolved with ethyl acetate
Residue, then organic phase is dried and is concentrated to give crude product with the 0.1M NaOH aqueous solution, washing respectively, purified by column chromatography,
It is dissolved in DMF, adds 50mg potassium fluorides, overnight, TLC detection raw material reactions is complete for 80 DEG C of reactions.Evaporated under reduced pressure solvent,
Residue with Ethyl acetate dissolves, and uses 0.1M Na2CO3The aqueous solution is washed twice, and organic phase is dried, and is evaporated and is obtained sodium salt, is drained
Into colorless foamy solid 40mg, yield 76%.
1H NMR (400MHz, CDCl3) δ 8.05-7.85 (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=10.0Hz, 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)
The preparation (7) of the 20-epi-20-O- p-nitrophenyl formoxyl Salinomycin Sodiums of embodiment 7
25mg intermediates 2 are dissolved in DMF, 25mg potassium fluorides are added, overnight, TLC detects raw material reaction for 80 DEG C of reactions
Completely.Evaporated under reduced pressure solvent, residue with Ethyl acetate dissolving, uses 0.1M Na2CO3The aqueous solution is washed twice, and organic phase is dried,
It is evaporated and obtains sodium salt, drains into colorless foamy solid 10mg, yield 40%.
1H NMR (400MHz, CDCl3) δ 8.31 (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=12.4,5.6Hz, 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)
Preparations (8) of the 20-epi-20-O- of embodiment 8 to TRIFLUOROMETHYLBENZOYL Salinomycin Sodium
50mg intermediates 3 are dissolved in 2ml dichloromethane, 100 μ L is added to trifluoromethyl benzoyl chloride, the second of 150 μ L tri-
Amine and 5mg DMAP, during 50 DEG C of stirrings 12, TLC detection raw material reactions are complete, add methyl alcohol that reaction is quenched.Solvent evaporated, uses acetic acid
Ethyl ester dissolution residual substance, then organic phase is dried and is concentrated to give crude product with the 0.1M NaOH aqueous solution, washing respectively, by post layer
Analysis purifying.It is dissolved in DMF, adds 50mg potassium fluorides, overnight, TLC detection raw material reactions is complete for 80 DEG C of reactions.Decompression is steamed
Dry solvent, residue with Ethyl acetate dissolving, uses 0.1M Na2CO3The aqueous solution is washed twice, and organic phase is dried, and is evaporated and is obtained sodium
Salt, drains into colorless foamy solid 40mg, yield 72%.
1H NMR (400MHz, Chloroform-d) δ 8.07 (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)
The preparation (9) of the 20-epi-20-O- furans -2- formoxyl Salinomycin Sodiums of embodiment 9
50mg intermediates 3 are dissolved in 2ml dichloromethane, add 100 μ L furans -2- formyl chlorides, 150 μ L triethylamines and
5mg DMAP, during 50 DEG C of stirrings 12, TLC detection raw material reactions are complete, add methyl alcohol that reaction is quenched.Solvent evaporated, uses ethyl acetate
Dissolution residual substance, then organic phase is dried and is concentrated to give crude product with the 0.1M NaOH aqueous solution, washing respectively.It is dissolved in DMF
In, 50mg potassium fluorides are added, overnight, TLC detection raw material reactions are complete for 80 DEG C of reactions.Evaporated under reduced pressure solvent, residue second
Acetoacetic ester dissolves, and uses 0.1M Na2CO3The aqueous solution is washed twice, and organic phase is dried, and is evaporated and is obtained sodium salt, drains into colourless foam
Shape solid 40mg, yield 78.5%.
1H NMR (400MHz, Chloroform-d) δ 7.59 (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 example part
The anti tumor activity in vitro experiment of 1 20 epimerization salinomycins of test example and acylate
Experimental technique
(1) from tetra- kinds of tumour cells of adherent A549, Bel7402, HCT-8 of exponential phase, digested with pancreatin respectively
Afterwards, the cell suspension of 15000/ml is made into the RPMI1640 nutrient solutions of 10% calf serum, is seeded in 96 well culture plates,
190ul, 37 DEG C, 5%CO are inoculated with per hole2Culture 24h.
(2) experimental group sample-adding product 10ul, per hole final volume position 200ul, is supplied with RPMI-1640.37 DEG C, 5%CO2Training
Support 3d.
(3) supernatant is abandoned, the serum-free medium of the 0.5mg/mlMTT of 100ul Fresh, 37 DEG C of continuation is added per hole
Culture 4h.It is careful to abandon supernatant, and add 150ul DMSO to dissolve MTT formazon precipitations, mixed with miniature ultrasonic oscillator,
The OD value at wavelength 570nm is determined on ELIASA.
(4) growth of tumour cell inhibiting rate is calculated.
As a result：Test compound anti tumor activity in vitro IC50(μM)*
Result shows that 20 epimerization salinomycins and acylate have significant antitumor activity in vitro.
Wherein, the pharmacological activity of compound 3,4 and 6 enhances more than 10 times than parent compound salinomycin, and the wherein pharmacology of compound 4 is lived
Property preferably, the inhibitory action to liver cancer Bel7402 tumour cells improves more than 50 times than 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.
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| WO2017202295A1 (en) * | 2016-05-24 | 2017-11-30 | 中国医学科学院药物研究所 | Salinomycin oxime ether derivative, preparation method therefor, and antitumor use thereof |
| CN115052879A (en) * | 2020-02-07 | 2022-09-13 | 菲莱克洛有限责任公司 | Compound consisting of C20 modified salinomycin derivatives, method for obtaining same, composition comprising same, use of said compound and method for obtaining intermediate product |
| CN115052879B (en) * | 2020-02-07 | 2024-05-10 | 菲莱克洛有限责任公司 | Compounds consisting of C20 modified salinomycin derivatives, process for obtaining them, compositions comprising them, use of the compounds and process for obtaining intermediates |
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