Tetravalent platinum glycosyl complex for tumor treatment and preparation method thereof

A tumor treatment, tetravalent platinum technology, applied in the preparation of sugar derivatives, medical preparations containing active ingredients, sugar derivatives, etc. The effect of improving ester-water partition coefficient, increasing maximum tolerated dose, and increasing bioavailability

Inactive Publication Date: 2019-07-02
NANKAI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, the biggest disadvantages of divalent platinum-based antineoplastic drugs are strong toxic and side effects, low in vivo availability, poor stability, and short half-life. Disadvantages of oral medication
Due to the poor water solubility of these drugs, it brings great difficulties to clinical drug use. After intravenous injection of 100mM cisplatin into the body, less than 1% of them finally bind to tumor cell DNA and play a role. Most cisplatin is compatible with Proteins in the body were combined, which reduced bioavailability and increased toxic side effects. Later, carboplatin and oxaliplatin were used in clinical practice, which improved the reactivity of cisplatin to DNA structurally, but did not fundamentally Solve the shortcomings of poor solubility and inability to take orally

Method used

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  • Tetravalent platinum glycosyl complex for tumor treatment and preparation method thereof
  • Tetravalent platinum glycosyl complex for tumor treatment and preparation method thereof
  • Tetravalent platinum glycosyl complex for tumor treatment and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] Embodiment 1: the synthesis of tetravalent cisplatin carboxylic acid

[0060]

[0061] C2 HRMS: Calcd.for Cl 2 h 8 N 2 o 2 Pt(M + ):332.96,found:332.9827.

[0062] C3 HRMS: Calcd.for C 4 h 12 Cl 2 N 2 o 5 Pt(M + ):432.98,found:432.9847.

Embodiment 2

[0063] Example 2: Synthesis of Glycosylated Tetravalent Platinum Final Product A1

[0064]

[0065] The preparation method is as follows: C1 (divalent platinum compound cisplatin) is oxidized with hydrogen peroxide at 60-70°C and reacted for 4 hours to prepare C2 tetravalent cisplatin compound; C2 (1equiv) and succinic anhydride ( 4equiv) was dissolved in DMF, reacted overnight at 70°C under nitrogen protection, and then the oil pump was drained. After adding dichloromethane to precipitate a solid, C4 could be prepared by washing with chloroform, ether, etc.; the DMF solution of C4 was mixed with 2-(7 -Azobenzotriazole)-N,N,N',N'-Tetramethyluronium hexafluorophosphate DMF solution was mixed and stirred for 10 minutes, then added full acetylated glucosamine and N,N-di The DMF mixture of isopropylethylamine was reacted at room temperature in the dark for 24 hours to obtain A1.

[0066] A1: 1 H NMR (400MHz, CDCl 3 )δ6.41(d,J=146.8Hz,4H),5.47–4.79(m,14H),4.64–4.08(m,5H),4.02...

Embodiment 3

[0067] Example 3: Synthesis of Glycosylated Tetravalent Platinum Final Product A2

[0068]

[0069] The preparation method is as follows: C1 (divalent platinum compound cisplatin) is oxidized with hydrogen peroxide at 60-70°C and reacted for 8 hours to prepare C2 tetravalent cisplatin compound; C2 (1equiv) and succinic anhydride ( 4equiv) was dissolved in DMF, reacted overnight at 70°C under nitrogen protection, and then the oil pump was drained. After adding dichloromethane to precipitate a solid, C4 could be prepared by washing with chloroform, ether, etc.; the DMF solution of C4 was mixed with 2-(7 -Azobenzotriazole)-N,N,N',N'-Tetramethyluronium hexafluorophosphate DMF solution was mixed and stirred for 20 minutes, then added full acetylated rhamnosamine and N,N - DMF mixed solution of diisopropylethylamine, A2 was obtained after reaction at room temperature in the dark for 48 hours.

[0070] A2: 1 H NMR (400MHz, CDCl 3 )δ5.28(s,6H),5.22–4.89(m,5H),4.72(s,1H),3.78(d,J...

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Abstract

The invention provides a quadrivalent-platinum glycosyl complex for treating tumors and a preparation method thereof. The synthesized compound has good anti-tumor activity better than that of cisplatin and oxaliplatin, and has better stability than that of bivalent platinums such as cisplatin, carboplatin and oxaliplatin. In addition, since the quadrivalent platinum with galactosylated modification has better targeting for tumor cells, the high selectivity to the tumor cells is improved. Furthermore, the compound provided by the invention has the advantages that the problems of poor solubility and more troublesome clinical compatibility of the original bivalent-platinum anti-tumor medicine are solved, and both fat solubility and water solubility are better. The quadrivalent-platinum glycosyl derivative not only can improve the in-vivo availability and enhance the curative effect, but also can reduce the toxic and side effects of the original bivalent-platinum medicine on the kidney and the like.

Description

technical field [0001] The invention relates to a platinum complex, in particular to a glycosyl-containing tetravalent platinum complex for tumor treatment and a preparation method of the complex. Background technique [0002] For a long time, tumors have been medically difficult to cure diseases. In the past, while drug treatment killed tumor cells, it also produced toxicity to normal cells, which caused various complications caused by drug treatment. Therefore, for tumor cells Targeted therapy has always been the focus of research. Only by selectively killing tumor cells can this major problem that threatens human health be solved. [0003] Platinum metal drugs are one of the representative drugs for anti-tumor treatment. In 1967, cisplatin was found to have anti-tumor activity. After that, it also became an anti-tumor drug with a long history and long application time. With the second generation of carboplatin and the first The third generation of oxaliplatin is graduall...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H23/00C07H1/00A61K31/7135A61P35/00
CPCC07H1/00C07H23/00
Inventor 王欣王鹏马静
Owner NANKAI UNIV
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