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Anti-tumor tetravalent platinum complex with anti-drug resistance function and preparation method thereof

A technology of platinum complexes and tetravalent platinum, applied in the field of medicine, can solve problems such as toxic side effects, drug resistance, and limited clinical use, and achieve low toxicity, excellent cytotoxic activity, and excellent antitumor effect

Active Publication Date: 2020-05-29
NANJING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Nevertheless, platinum-based drugs have also encountered some difficulties and problems, mainly including toxic side effects and drug resistance, which greatly limit their wider clinical use

Method used

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  • Anti-tumor tetravalent platinum complex with anti-drug resistance function and preparation method thereof
  • Anti-tumor tetravalent platinum complex with anti-drug resistance function and preparation method thereof
  • Anti-tumor tetravalent platinum complex with anti-drug resistance function and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Synthesis of Tetravalent Platinum Complexes 1 and 2

[0029]

[0030] S1. Put 1 g of Cisplatin in a flask, add 60 mL of 30% hydrogen peroxide dropwise, heat it to 75°C in the dark and stir for 6 hours, place it at room temperature for two days, and place it in a refrigerator at 4°C for two days, filter and vacuum dry. Obtain tetravalent Oxoplatin yellow powder;

[0031] S2, take 100mg Oxoplatin, 191mg (or 204mg ), 125 μL of triethylamine (TEA) and 290 mg of O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroboric acid (TBTU) were dissolved in 10 mL of dry DMF, protected from light at room temperature Stir for 48h;

[0032] S3, after the reaction is finished, the precipitate is removed by filtration, the reaction solution is concentrated under reduced pressure to 5 mL, 20 mL of a 1:1 mixture of ethanol and water is added, a pale yellow solid is precipitated, and washed twice with methanol and ether respectively to obtain a pure solid, The yield is about 80%. ...

Embodiment 2

[0033] Example 2 Cytotoxicity test of compounds 1 and 2

[0034] The compounds 1 and 2 prepared in Example 1 of the present invention were tested for their cytotoxic activity, respectively using A549 / DDP, A549, A2780 / DDP, A2780, MCF-7, Caov3 and L-02 cells as models, and synthesized in Example 1. The compounds 1, 2 and cisplatin are the substances to be detected. After the substances to be detected are applied to the cells, the survival of the cells is observed, and the cell survival rate is tested by the thiazolyl blue (MTT) method. The specific operation steps are as follows:

[0035] S1. Collect the above log phase cells, adjust the concentration of the cell suspension, and add them to a 96-well plate, with about 5,000 cells per well;

[0036] S2. The above experimental cells were placed in a cell incubator with a CO2 concentration of 5%, and cultured at 37°C for 12 hours;

[0037] S3. Compounds 1, 2 and cisplatin were diluted with a medium containing 10% FBS according to ...

Embodiment 3

[0046] Example 3 In vivo tumor inhibition test of compounds 1 and 2

[0047] After subcutaneously implanting human non-small cell lung cancer A549 cells into nude mice and forming tumors, the mice were divided into cages and groups, with 5 mice in each group;

[0048] The mice were administered by tail vein injection, cisplatin 2 mg / kg, compounds 1 and 2 were both 4 mg / kg, administered once every three days and the tumor volume and the weight of the mice were measured. The results are as follows: Figure 7 and 8 shown.

[0049]Compared with traditional divalent platinum complexes, tetravalent platinum complexes have two more ligands in the axial direction and form an octahedral structure in space, so they are kinetically inert, have lower reactivity and less toxicity. side effect. It is generally believed that tetravalent platinum complexes remain stable in plasma and normal tissues, and will be reduced to bivalent platinum complexes in tumor hypoxic and high reducing envir...

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Abstract

The invention provides an anti-tumor tetravalent platinum complex with an anti-drug resistance function and a preparation method thereof. The structural formula of the compound is shown as a formula Ior a formula II, and the compound is one of the following structures: the compound has excellent cytotoxic activity to tumor cells, especially to cisplatin-resistant tumor cells, and shows excellenttumor inhibition effect and relatively low toxicity in vivo.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to an anti-tumor tetravalent platinum complex with anti-drug resistance function and a preparation method. Background technique [0002] Platinum complexes are one of the most widely used antitumor drugs, especially the first-generation platinum antitumor drug cisplatin, which is very effective for reproductive system cancers and head and neck cancers. It has been approved by the FDA in 1978. Since cancer, the mortality rate of testicular cancer patients has been reduced from almost 100% to less than 10%, and the cure rate of patients with early detection can reach 100%, thus becoming an outstanding representative of anti-tumor drugs. Following cisplatin, in 1989, the FDA approved the second-generation platinum-based antitumor drug carboplatin to be marketed. Its anticancer spectrum is similar to cisplatin, but the side effects are milder. In 2002, the FDA approved the third-gen...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F15/00A61P35/00
CPCC07F15/0093A61P35/00
Inventor 王晓勇
Owner NANJING UNIV
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