Melatonin-platinum (IV)-carbon nitrogen long-chain complex, preparation method and application of melatonin-platinum (IV)-carbon nitrogen long-chain complex in tumor drugs

An anti-tumor drug, melatonin technology, applied in the application, preparation, and field of melatonin-platinum-carbon-nitrogen long-chain complexes in tumor drugs, can solve the problem of concentrated effect time and improve the body's immunity Power, less side effects, the effect of regulating biological rhythm

Pending Publication Date: 2022-08-02
TIANJIN MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The inventor’s prior application for patent No. 2018115158228 discloses a structure in which melatonin molecules are connected to one side of the platinum (IV) coordination or opposite sides, and proves its anti-tumor effect compared to cisplatin alone The effect has been significantly improved, but the duration of the effect is relatively concentrated

Method used

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  • Melatonin-platinum (IV)-carbon nitrogen long-chain complex, preparation method and application of melatonin-platinum (IV)-carbon nitrogen long-chain complex in tumor drugs
  • Melatonin-platinum (IV)-carbon nitrogen long-chain complex, preparation method and application of melatonin-platinum (IV)-carbon nitrogen long-chain complex in tumor drugs
  • Melatonin-platinum (IV)-carbon nitrogen long-chain complex, preparation method and application of melatonin-platinum (IV)-carbon nitrogen long-chain complex in tumor drugs

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Experimental program
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preparation example Construction

[0072] Wherein, the preparation method of the compound of formula 21 comprises:

[0073] The melatonin of formula 24 and the compound of formula 25 (succinic anhydride or glutaric anhydride) are subjected to acylation reaction in the presence of the second condensing agent and the second acid binding agent to obtain the compound of formula 11;

[0074]

[0075] Wherein, the second condensing agent is DMAP; the second acid binding agent is triethylamine.

[0076] The above-mentioned melatonin-platinum (IV)-carbon-nitrogen long-chain complex can be used to prepare anti-tumor drugs, for example, can be used to prepare anti-ovarian cancer, cervical cancer, breast cancer, lung cancer, liver cancer, intestinal and gastric cancer drugs; especially suitable for sex hormones Related tumors ovarian cancer, cervical cancer, breast cancer drugs.

Embodiment 1

[0079] The structural formula of the melatonin-platinum (IV)-carbon nitrogen long-chain complex a of this embodiment is as follows:

[0080]

[0081] The synthesis route of the preparation method of the melatonin-platinum (IV)-carbon nitrogen long-chain complex described in this embodiment is as follows:

[0082]

[0083]

[0084] In step 1, cisplatin was oxidized under the condition of hydrogen peroxide for 6 h, and after the end, it was refrigerated at 0-4 °C overnight, and then washed with water, ice ethanol and ether to obtain a pale yellow precipitate Oxoplatin (c,c,t-[ Pt(NH 3 ) 2 Cl 2 (OH) 2 ]), a1.

[0085] Step 2, melatonin (MT) is reacted with succinic anhydride, 4-dimethylaminopyridine (DMAP) is added in the reaction, triethylamine (Et 3 N), protected with argon during the reaction, the reaction temperature was 50 °C for 48 h, the reaction solution was concentrated into oil and separated by silica gel chromatography column, the eluents were dichloromet...

Embodiment 2

[0090] The structural formula of the melatonin-platinum (IV)-carbon-nitrogen long-chain complex b of this embodiment is as follows:

[0091]

[0092] The route is as follows:

[0093]

[0094]

[0095] In step 1, cisplatin was oxidized under the condition of hydrogen peroxide for 6 h, and after the end, it was refrigerated at 0-4 °C overnight, and then washed with water, ice ethanol and ether to obtain a pale yellow precipitate Oxoplatin (c,c,t-[ Pt(NH 3 ) 2 Cl 2 (OH) 2 ]), a1.

[0096] Step 2, melatonin (MT) is reacted with glutaric anhydride, 4-dimethylaminopyridine (DMAP) is added in the reaction, triethylamine (Et 3 N), protected with argon during the reaction, the reaction temperature was 50°C for 48h, the reaction solution was concentrated into oil and separated by silica gel chromatography column, the eluents were dichloromethane and methanol, and milky white precipitate b2 was obtained.

[0097] Step 3, mix the product b2 in step 2 with dry dimethyl sulf...

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Abstract

The invention discloses a melatonin-platinum (IV)-carbon nitrogen long-chain complex, a preparation method and application of the melatonin-platinum (IV)-carbon nitrogen long-chain complex in tumor drugs. Melatonin is introduced to one side of an axial site of a Pt (IV) coordination center, and a carbon-nitrogen long chain is introduced to the other side, so that the lipophilicity of the complex is improved; compared with an unmodified platinum drug, the drug in the system has better tumor killing ability, the cytotoxicity is increased by dozens of times compared with cis-platinum, and particularly, the killing effect on sex hormone related tumors such as ovarian cancer, cervical cancer and breast cancer cells is more obvious; meanwhile, the melatonin reduces the drug resistance of cis-platinum besides the potential anti-tumor effect, and compared with a pure melatonin-platinum (IV) complex, the melatonin has a better slow release effect. The medicine is simple in synthesis process and low in cost, the curative effect of drug combination is greatly improved, compared with traditional bivalent platinum and similar tetravalent platinum drugs, the medicine has the advantages of being good in curative effect, small in side effect and the like, and a new thought is provided for modification of tetravalent platinum.

Description

technical field [0001] The invention belongs to the technical field of anticancer chemical drugs, and in particular relates to a melatonin-platinum (IV)-carbon-nitrogen long-chain complex, a preparation method and its application in tumor drugs. Background technique [0002] Cancer has now become a great threat to human health. The current clinical treatments for cancer are surgery, radiotherapy, and chemotherapy. Surgical resection can only target most concentrated areas of tumor tissue and cannot completely eradicate cancer cells. Radiation therapy is highly localized in cancer treatment. It is mainly suitable for residual cancer cells during the excision of primary lesions, concentration of metastatic lesions, or postoperative prevention. The scope of application is small and systemic control cannot be achieved. With certain damage, radiation pneumonitis is prone to occur. Therefore, chemotherapy is still an important strategy for comprehensive treatment of breast canc...

Claims

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Application Information

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IPC IPC(8): C07F15/00A61K31/555A61K47/55A61P35/00
CPCC07F15/0093A61K47/55A61P35/00
Inventor 徐靖源刘瑞苹刘晓萌李哲
Owner TIANJIN MEDICAL UNIV
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