C20 site epimerization salinomycin and derivatives thereof, and preparation method and use thereof

A technology of epimerization and salinomycin, applied in organic chemistry, drug combination, pharmaceutical formulation, etc., can solve the problems of in-depth research on activity testing and unclear structure-activity relationship

Active Publication Date: 2017-06-06
INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But in general, the modification strategy is relatively simple, there are not many synthetic derivative

Method used

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  • C20 site epimerization salinomycin and derivatives thereof, and preparation method and use thereof
  • C20 site epimerization salinomycin and derivatives thereof, and preparation method and use thereof
  • C20 site epimerization salinomycin and derivatives thereof, and preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0058] The preparation of preparation example 1 salinomycin trimethylsilyl ethyl ester (intermediate 1)

[0059]

[0060] 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.

[0061] 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(...

preparation example 220

[0062] Preparation 2 20-epi-20-O-p-nitrobenzoyl salinomycin trimethylsilyl ethyl ester (intermediate 2)

[0063]

[0064] 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%.

[0065] 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...

preparation example 320

[0066] Preparation Example 3 Preparation of 20-epi-salinomycin trimethylsilyl ethyl ester (intermediate 3)

[0067]

[0068] 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.

[0069] 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=...

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Abstract

The invention belongs to the field of pharmaceutical chemistry, and relates to C20 site epimerization salinomycin and acylated derivatives thereof, and a preparation method and an anti-tumor use thereof, especially a use in preparation of drugs for resisting lung cancer, colon cancer and liver cancer.

Description

technical field [0001] 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 [0002] 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. [0003] 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 ...

Claims

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Application Information

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IPC IPC(8): C07D493/20A61K31/351A61P35/00
CPCC07D493/20
Inventor 吴松杜冠华张文轩何国荣李莉
Owner INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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