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Preparation method and anti-tumor application of phosphonate glycoside derivative

A technology of glycoside derivatives and phosphonate esters, which is applied in the field of antitumor drugs and can solve the problems of high toxicity and side effects

Inactive Publication Date: 2018-07-06
ZUNYI MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

At the same time, most of the anti-tumor drugs have serious side effects and tumor cell drug resistance, which makes the existing drug treatment encounter great challenges

Method used

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  • Preparation method and anti-tumor application of phosphonate glycoside derivative
  • Preparation method and anti-tumor application of phosphonate glycoside derivative
  • Preparation method and anti-tumor application of phosphonate glycoside derivative

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0011] The preparation method of target phosphonate glycoside derivative (Ⅲ): R is a chain substituent of 1-6 atoms or a cycloalkyl or aromatic hydrocarbon group of 3-6 atoms, X is H or one halogen or multiple halogens or nitro or a chain substituent of 1-3 atoms Or aromatic group, the configuration of the 2,3,4 acetoxy group in the sugar structure can be a horizontal bond (e bond) or a vertical bond (a bond). Its synthetic reaction formula is:

[0012]

[0013] O,O'-diethyl-α-(2-fluorophenyl)-α-(2′,3′,4′,6′-tetra-O-acetyl-β-D-glucopyranosyl) Preparation of Methylphosphonate (Ⅲa)

[0014] Add 2.2mmol of 1-bromo-2′,3′,4′,6′-tetra-O-acetyl-β-D-glucopyranose and 0.6mmol of [Bmim]OH ionic liquid into the three-neck flask, Then add 2.4mmol tetrabutylammonium bromide, O, O'-diethyl-α-(2-fluorophenyl)-α-hydroxymethyl phosphonate 2.0mmol, 50ml chloroform and 50ml purified water. Put it in a microwave synthesizer, react at a microwave power of 900W and a reaction temperature o...

Embodiment 2

[0016] O,O'-diethyl-α-phenyl-α-(2',3',4',6'-tetra-O-acetyl-β-D-galactopyranosyl)-methylphosphine Preparation of acid ester (Ⅲb)

[0017] 2.0mmol of 1-bromo-2′,3′,4′,6′-tetra-O-acetyl-β-D-galactopyranose, [Emim]Cl-AlCl 3 Add 0.6mmol of ionic liquid into the three-neck flask, then add 2.4mmol of tetrabutylammonium bromide and 2.2mmol of O,O'-diethyl-α-phenyl-α-hydroxymethylphosphonate into the reaction flask , 60ml chloroform and 60ml purified water. Place in a microwave synthesizer, react for 70min at a microwave power of 1000W and a reaction temperature of 40°C, stop the reaction, separate the liquid with a separatory funnel, concentrate chloroform to obtain a crude product, separate and purify by column chromatography, and obtain the target compound (Ⅲb) as Yellow viscous liquid, yield 86.9%. 1 H-NMR (400MHz, CDCl 3 )δ:7.12-7.26(m,5H,ArH),5.55(d,1H,J=10.8Hz,OCHO),4.98-5.44(m,4H,4OCH),4.02-4.16(m,7H,PCH+2OCH 2 ),1.90-2.06(m,12H,4COCH 3 ),1.10-1.18(m,6H,2CH 3 ). 13 C-NM...

Embodiment 3

[0019] Antitumor activity test

[0020] The antitumor activity of the prepared phosphonate glycoside derivatives was measured by MTT method with cisplatin as the control. The results showed that the target compounds had proliferation inhibitory activity on human esophageal cancer cell EC-109, such as: compound O,O'-di Ethyl-α-(2-fluorophenyl)-α-(2′,3′,4′,6′-tetra-O-acetyl-β-D-mannopyranosyl)methylphosphonate The IC50 for EC-109 is 8.4±1.3μmol / L, the compound O,O'-diethyl-α-(4-fluorophenyl)-α-(2′,3′,4′,6′-tetra The IC50 of -O-acetyl-β-D-galactopyranosyl)methylphosphonate to EC-109 was 7.5±1.0μmol / L, which was close to that of the control drug.

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Abstract

The invention discloses a preparation method and anti-tumor application of a phosphonate glycoside derivative and belongs to the field of researches of anti-tumor drugs. In order to obtain an anti-tumor candidate compound, an existing medical chemical theory is adopted to design a series of phosphonate glycoside derivatives with brand-new structures; the preparation method comprises the followingsteps: taking a bromoacetylated monosaccharide intermediate and a hydroxyl phosphonate intermediate as raw materials and reacting in a microwave synthesizer under an alkaline ion catalysis condition to prepare the phosphonate glycoside derivative shown as (III). The derivative has a proliferation inhibition effect on esophageal cancer cells EC-109 and can be further used for researching anti-tumorcompounds.

Description

technical field [0001] The invention relates to an antitumor drug, in particular to a phosphonate glycoside derivative, a preparation method thereof and an antitumor application. Background technique [0002] Statistics from the World Health Organization (WHO) show that the global tumor morbidity and mortality are still high, especially in developing countries, and tumors are becoming the number one killer threatening human health in the new century. The mortality rate of malignant tumors in my country's urban and rural areas is at a high level in the world, and it shows a continuous growth trend every year. At the same time, most of the anti-tumor drugs have serious side effects and drug resistance of tumor cells, which make the existing drug treatment encounter great challenges. Therefore, it is of great significance to develop anti-tumor drugs with novel structures and promising research prospects. [0003] Based on the above reasons, combined with the existing research...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H13/04C07H1/02A61P35/00
CPCC07H1/02C07H13/04
Inventor 杨家强陈磊王刚熬慧杨璇朱勇
Owner ZUNYI MEDICAL UNIVERSITY
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