Quadrivalent platinum complex with functions of targeted inhibition of AKR1C3 and reversal of tumor drug resistance and preparation method thereof

A platinum complex, tetravalent platinum technology, applied in anti-tumor drugs, pharmaceutical formulations, platinum group organic compounds, etc., to achieve good stability, significant anti-tumor efficacy, and reversal of tumor drug resistance.

Pending Publication Date: 2021-07-16
HENAN UNIV OF URBAN CONSTR
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, studies have confirmed that AKR1C3 is also abnormally expressed in non-hormone-related cancers and is associated with resistance to chemotherapy drugs such as cisplatin and 5-fluorouracil

Method used

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  • Quadrivalent platinum complex with functions of targeted inhibition of AKR1C3 and reversal of tumor drug resistance and preparation method thereof
  • Quadrivalent platinum complex with functions of targeted inhibition of AKR1C3 and reversal of tumor drug resistance and preparation method thereof
  • Quadrivalent platinum complex with functions of targeted inhibition of AKR1C3 and reversal of tumor drug resistance and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Tetravalent platinum complex (formula I), hereinafter referred to as the preparation of compound 1:

[0049] S1. Weigh 1 g of cisplatin and place it in a single-necked flask, slowly add 50 mL of 30% hydrogen peroxide dropwise into the single-necked flask, heat the mixture to 75°C, stir for 4 hours in the dark, place in a refrigerator at 4°C for two days, filter and vacuum After drying, the oxidized tetravalent cisplatin precursor (Oxoplatin) yellow powder is obtained;

[0050] S2, take 648.6mg and 258.9mg of N-N-hydroxysuccinimide (NHS), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) were added to 15mL of anhydrous DMF, and stirred at room temperature for 24h for esterification chemical reaction, making (B-ester), standby;

[0051] S3. Weigh 100 mg of Oxoplatin prepared by S1 and 125 mg of B-ester prepared by S2, dissolve in 10 mL of anhydrous DMF, and carry out the reaction at 60° C. in the dark and stir overnight;

[0052] S4. After the reaction, remove...

Embodiment 2

[0054] Tetravalent platinum complex (formula II), hereinafter referred to as the preparation of compound 2:

[0055] S1. Weigh 1 g of cisplatin and place it in a single-necked flask, slowly add 50 mL of 30% hydrogen peroxide dropwise into the single-necked flask, heat the mixture to 75°C, stir for 4 hours in the dark, place in a refrigerator at 4°C for two days, filter and vacuum After drying, the oxidized tetravalent cisplatin precursor (Oxoplatin) yellow powder is obtained;

[0056] S2. Weigh 100mg of Oxoplatin prepared by S1, 285mg 299 mg of O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroboric acid (TBTU) was dissolved in 10 mL of anhydrous DMF, and then 125 μL of triethylamine (TEA) was added to Stir in the dark for 48 hours at room temperature;

[0057] S3, after the reaction is finished, remove the precipitate by high-speed centrifugation, concentrate the remaining liquid material under reduced pressure, then add it dropwise to the mixed solution of ethanol a...

Embodiment 3

[0059] Tetravalent platinum complex (formula II), hereinafter referred to as the preparation of compound 2:

[0060] S1. Weigh 1g of oxaliplatin in a single-necked flask, slowly add 50mL of 30% hydrogen peroxide dropwise into the single-necked flask, heat the mixture to 75°C, stir for 4h in the dark, place in a refrigerator at 4°C for three days, and filter , After vacuum drying, the oxidized tetravalent oxaliplatin precursor (Oxaplatin) light yellow powder is obtained;

[0061] S2. Weigh 129mg of Oxalatin prepared by S1, 95mg 100 mg of O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroboric acid (TBTU) was dissolved in 10 mL of anhydrous DMF, and then 46 μL of triethylamine (TEA) was added to Stir in the dark for 48 hours at room temperature;

[0062] S3. After the reaction is over, remove the precipitate by high-speed centrifugation, concentrate the remaining liquid material under reduced pressure, then add dropwise to 10mL methanol and mix evenly, then add the solu...

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Abstract

The invention discloses a tetravalent platinum complex with functions of targeted inhibition of AKR1C3 and reversal of tumor drug resistance and a preparation method thereof. The preparation method is simple in process, convenient to operate, safe to operate and good in product stability. The prepared target tetravalent platinum complex shows a relatively strong AKR1C3 inhibition effect on a cellular level, shows relatively good proliferation inhibition activity on tumor cells without drug resistance and cisplatin-resistant tumor cells, and can promote apoptosis of the tumor cells by inducing autophagy, so that a relatively good tumor treatment effect is achieved. The target tetravalent platinum complex is clear in targeting and small in toxic and side effects, and can be used as a novel anti-tumor drug to cope with increasingly severe anti-cancer situations.

Description

technical field [0001] The invention relates to the technical field of anti-tumor tetravalent platinum complexes, in particular to a tetravalent platinum complex capable of targeting and inhibiting AKR1C3 and reversing tumor drug resistance and a preparation method thereof. Background technique [0002] The discovery of platinum-based metal drugs represented by cisplatin and its successful clinical application make metal anti-tumor drugs a milestone in the treatment of cancer. The early cure rate of cisplatin for testicular cancer has reached 95%. In addition to being used in the treatment of testicular cancer, cisplatin as an anticancer drug is also widely used in the first-line treatment of various malignant tumors including the head, neck and reproductive system. in the treatment plan. However, due to the poor selectivity of traditional platinum-based drugs to tumor cells, it often leads to indiscriminate killing of cells, which brings serious side effects during use. M...

Claims

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Application Information

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IPC IPC(8): C07F15/00A61K33/243A61K31/555A61P35/00
CPCC07F15/0093A61K33/243A61P35/00
Inventor 郭艳胡继勇赵金安
Owner HENAN UNIV OF URBAN CONSTR
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