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Tetravalent platinum complex containing artesunate as well as preparation method and application of tetravalent platinum complex

A technology of artesunate and tetravalent platinum, applied in the field of medicine, can solve the problems of difficult anti-tumor drugs and low anti-tumor activity, achieve excellent anti-tumor activity, solve drug resistance, and excellent synergistic anti-tumor effect

Pending Publication Date: 2021-07-06
FOURTH MILITARY MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although artesunate exhibits a unique anti-tumor mechanism, its anti-tumor activity is still relatively low, and its IC for a variety of tumor cell lines 50 It is tens of μM, it is difficult to develop into an anti-tumor drug alone
[0004] The patent application whose publication number is CN105906667A has reported that R 3 Quaternary platinum complexes that are hydroxyl-substituted or artesunate-disubstituted, but their anti-tumor activity is low, and the IC for many tumor cells tested 50 The range is 6.72μM~30.3μM, the overall performance is comparable to cisplatin

Method used

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  • Tetravalent platinum complex containing artesunate as well as preparation method and application of tetravalent platinum complex
  • Tetravalent platinum complex containing artesunate as well as preparation method and application of tetravalent platinum complex
  • Tetravalent platinum complex containing artesunate as well as preparation method and application of tetravalent platinum complex

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Synthesis of compound 1:

[0047]

[0048] Take 1.0 g of cisplatin, compound III, and add 25 mL of 30% hydrogen peroxide, react at 60° C. for 2 h, filter with suction, and leave the filtrate to obtain 0.95 g of oxoplatin, compound IV, as a yellow needle-like solid, with a yield of 85%.

[0049]

[0050] Dissolve 1.0 g of dihydroartemisinin, compound V (3.5 mmol) and 1.05 g of succinic anhydride (10.5 mmol) in 20 mL of acetonitrile solvent, stir at room temperature overnight, and purify by column chromatography (petroleum ether: ethyl acetate=5 : 1) Preparation of artesunate compound VI, white solid 1.05g.

[0051]

[0052] Artesunate, compound VI (50mg, 0.13mmol), TBTU (48mg, 0.15mmol) and triethylamine (15mg, 0.15mmol) were sequentially added to 2mL of dry DMF, stirred at room temperature for 10min, and oxygen platinum, compound IV was added (36mg, 0.11mmol), stirred at room temperature for 12h under nitrogen protection. After the reaction, the solvent was e...

Embodiment 2

[0056] Synthesis of compound 2

[0057]

[0058] Referring to the method steps of Example 1, compound VII (30 mg, 0.042 mmol) and n-hexanoic anhydride (11 mg, 0.051 mmol) were reacted in DMF (2 mL) to obtain light yellow solid compound 2 (22 mg, yield 64%).

Embodiment 3

[0060] Synthesis of Compound 3

[0061]

[0062] Referring to the method steps of Example 1, compound VII (30 mg, 0.042 mmol) was reacted with n-octylic anhydride (15 mg, 0.055 mmol) in DMF (2 mL) to obtain light yellow solid compound 3 (23 mg, yield 65%).

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Abstract

The invention discloses a tetravalent platinum complex containing artesunate. The structure of the tetravalent platinum complex is shown as a general formula I or II, wherein R is shown in the specification, and R1 is a branched chain or straight chain saturated C1-C20 alkyl group, or a branched chain or straight chain unsaturated C1-C20 alkyl group. The tetravalent platinum complex containing artesunate provided by the invention has an obvious proliferation inhibition effect on liver cancer HepG2, lung cancer A549, intestinal cancer HCT116, breast cancer MDA-MB-231 and cis-platinum drug-resistant lung cancer, the anti-tumor activity of part of compounds is obviously superior to that of cis-platinum, and the tetravalent platinum complex containing artesunate can be used as anti-tumor candidate drugs for deeper research.

Description

technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to a tetravalent platinum complex containing artesunate, a preparation method and its application in the preparation of antitumor drugs. Background technique [0002] Platinum antineoplastic drugs are widely used clinically in the treatment of malignant tumors. At present, the US FDA has approved three platinum drugs for marketing, including cisplatin, carboplatin and oxaliplatin. Cisplatin can be clinically effective against various solid tumors such as ovarian cancer, prostate cancer, testicular cancer, lung cancer, nasopharyngeal cancer, esophageal cancer, malignant lymphoma, head and neck squamous cell carcinoma, thyroid cancer and osteosarcoma. Carboplatin is the second-generation platinum drug. It is a broad-spectrum antineoplastic drug and has no cross-resistance with other anti-tumor drugs. It has cross-resistance with cisplatin. It is mainly used for small cell...

Claims

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Application Information

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IPC IPC(8): C07F15/00A61P35/00A61K31/555
CPCC07F15/0093A61P35/00
Inventor 王胜正
Owner FOURTH MILITARY MEDICAL UNIVERSITY
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