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Platinum diphosphonate complex as well as synthesis method and application thereof

A technology of platinum complexes and synthesis methods, applied in the field of chemical biology, can solve the problems of reduced curative effect and achieve the effects of alleviating drug resistance, high synthesis yield and reducing side effects

Pending Publication Date: 2022-04-15
NANJING MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

GSH acts as a nucleophile to chelate platinum(II) to form Pt(GS) 2 Chelates can reduce the DNA damage caused by divalent platinum, resulting in reduced efficacy of platinum-based drugs

Method used

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  • Platinum diphosphonate complex as well as synthesis method and application thereof
  • Platinum diphosphonate complex as well as synthesis method and application thereof
  • Platinum diphosphonate complex as well as synthesis method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] The synthetic method of bisphosphonic acid platinum complex, comprises the steps:

[0041] S1: Synthesis of 2-chloromethylpyridine:

[0042] 2-Chloromethylpyridine hydrochloride (5.292g, 32mmol) was dissolved in distilled water (7mL), and sodium hydroxide (1.344g, 32mmol) was added to distilled water (14mL) to make an alkaline solution, and the above two solutions were After mixing, extraction was performed with chloroform, and the extracted chloroform layer was dried over anhydrous magnesium sulfate and the solvent was removed in vacuo. The filter residue was purified by distillation under reduced pressure to obtain light red 2-chloromethylpyridine.

[0043] S2: Synthesis of [1,3-bis(2-pyridyl)propane-2,2-diyl]bis(phosphonic acid)tetraethyl ester:

[0044] Under nitrogen protection conditions at 273K, 20 mL of anhydrous DMSO added with 2-[2-pyridylethylethyl] bis(phosphonic acid) tetraethyl ester (9.31 g, 24.56 mmol) was added to 60% NaH (1.08 g , 29.47mmol) in 20mL...

Embodiment 2

[0048] Explore the reactivity of the bisphosphonate platinum complex DBPP and GSH prepared in Example 1, the steps are as follows:

[0049] The bisphosphonate platinum complex DBPP (0.0056mmol) was dissolved in deuterium water and phosphate buffer solution (PBS7.87mM, pH 7.4, D 2 (0.5 mL) of the mixed solution, put the above liquid into the nuclear magnetic resonance tube. Add GSH (2.45mg, 0.0132mmol) to the same nuclear magnetic resonance tube, place the nuclear magnetic resonance tube in a 310K water bath for incubation, and use it at different time intervals 31 P NMR and 1 H NMR detects the solution in the tube, and the test results are shown in the attached Image 6 .

[0050] attached Image 6 a The data shows that the peak values ​​of DBPP are located at 24.88 and 20.09ppm respectively, and after 168h of cultivation, no significant change in the data has been observed, which shows that DBPP has a certain inertia to glutathione; attached Image 6 Similar results can ...

Embodiment 3

[0052] Explore the lipophilicity of the bisphosphonic acid platinum complex DBPP prepared in Example 1, the steps are as follows:

[0053] The lipophilicity coefficient was determined by n-octanol shake flask method. Add (50, 100, 150, 200μM) DBPP solutions to 10mM, pH 7.4 phosphate buffer solution respectively, mix 2.0mL of the above solutions with an equal volume of 1-octanol, and place on a constant temperature (25.0±0.1℃) air bath orbital shaker Centrifuge at 200rpm for 4h. After centrifuging at 2500rpm for 15min, the sample was divided into two phases; max =267nm) to measure the DBPP concentration in the aqueous solution, calculate the logarithmic P value of the DBPP concentration and the DBPP concentration in the n-octanol phase to obtain the fat-water partition coefficient of DBPP, the measurement results refer to the appendix Figure 7 , see the attached table 1 for the calculation results.

[0054] attached Figure 7 The data showed a regular distribution of DBPP ...

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Abstract

The invention discloses a diphosphonic acid platinum complex and a preparation method thereof, a non-leaving group of the complex is composed of ammonia and a diphosphonic acid bipyridine ligand, and the diphosphonic acid bipyridine ligand and a platinum center form an eight-membered ring. The synthesis method of the complex comprises synthesis of 2-chloromethylpyridine, synthesis of [1, 3-bis (2-pyridyl) propane-2, 2-diyl] bis (phosphonic acid) tetraethyl ester and synthesis of the diphosphonic acid platinum complex, and the synthesis method is high in synthesis yield, high in implementation feasibility and stable in product. The complex is difficult to chelate with glutathione, so that side effects caused by combination of platinum drugs and glutathione can be greatly reduced, and the complex can be used for overcoming drug resistance of the platinum drugs; the complex has a certain inhibition effect on osteosarcoma cells; the complex can also interact with human serum albumin in a static quenching manner. The research provides a new strategy for solving the drug resistance of the platinum diphosphonate, and good technical progress is achieved.

Description

technical field [0001] The invention belongs to the field of chemical biology, and in particular relates to the synthesis of a platinum bisphosphonate complex and its biological application. Background technique [0002] Cisplatin, also known as cis-dichlorodiammine platinum, is a clinically used platinum-based anticancer drug. Platinum anticancer drugs such as cisplatin can effectively improve the prognosis of osteosarcoma, increasing the 5-year survival rate of osteosarcoma patients to 60%-80%. The main mechanism of action of cisplatin is to inhibit the proliferation of rapidly dividing cells by damaging DNA, but the acquired drug resistance and severe side effects of cisplatin greatly limit the widespread use of platinum-based drugs. [0003] Glutathione (GSH) is a soluble tripeptide combined with glutamic acid, cysteine ​​and glycine. It is an abundant non-protein tripeptide in cells. It has antioxidant and integrated detoxification functions. The intracellular concent...

Claims

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Application Information

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IPC IPC(8): C07F15/00A61P35/00
Inventor 张振琴谢安琦居一春马露
Owner NANJING MEDICAL UNIV
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