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Cis-dammine dichloroplatinum prodrug, preparation method and application

A cisplatin and drug technology, applied in the field of medicinal chemistry and preparation, can solve the problems of poor water solubility of cisplatin, poor drug stability, low maximum tolerated dose, etc. Effect

Inactive Publication Date: 2018-12-18
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In order to solve the problems of poor water solubility of cisplatin, poor drug stability, and low maximum tolerated dose of the drug in vivo, the invention provides a cisplatin (CDDP) prodrug

Method used

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  • Cis-dammine dichloroplatinum prodrug, preparation method and application
  • Cis-dammine dichloroplatinum prodrug, preparation method and application
  • Cis-dammine dichloroplatinum prodrug, preparation method and application

Examples

Experimental program
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Effect test

Embodiment 1 2

[0060] The synthesis of embodiment 1 dihydroxy diamine dichloroplatinum II, such as figure 1 Shown:

[0061] A 100 mL round bottom flask was charged with CDDP (1 g, 3.33 mmol) and 15 ml of 30% hydrogen peroxide (30%, w / v). Stir at 75°C in the dark for 5 hours, cool at 4°C for 2 hours, filter under reduced pressure to obtain light yellow crystals, wash with water, ethanol and ether, and dry to obtain product II (998 mg, yield 90%).

Embodiment 2

[0062] Example 2 Synthesis of CDDP prodrug 1 containing saturated alkane chain compound, such as figure 2 Shown:

[0063] Add II (100mg, 0.3mmol) and n-hexanoic anhydride (127mg, 0.6mmol) to a 100mL round bottom flask, dissolve in (DMF), and add N,N'-dicyclohexylcarbodiimide (0.3mmol). Stir at 70°C for 3 hours. After the reaction, add water to precipitate a light yellow solid; then wash with water and petroleum ether, and filter to obtain product 1 (95 mg, yield 60%).

[0064] product 1 1 The H NMR nuclear magnetic data is as follows:

[0065] 1 H NMR(400MHz,DMSO-d6):δ0.84-0.88(t,6H),1.23-1.27(m,8H),1.42-1.51(m,4H),2.16-2.22(m,4H),6.38- 6.63 (m, 6H).

Embodiment 3

[0066] Example 3 Synthesis of CDDP prodrug 2 containing saturated alkane chain compound, such as image 3 Shown:

[0067] In a 100 mL round bottom flask, add II (100 mg, 0.3 mmol) and n-heptanoic anhydride (146 mg, 0.6 mmol), dissolve in 2 mL of anhydrous dimethylformamide (DMF), add 1-(3-dimethylaminopropyl )-3-Ethylcarbodiimide (0.3 mmol). Stir at 70°C for 3 hours, add water to precipitate after the reaction to obtain a yellowish solid; then wash with water and petroleum ether, and filter to obtain product 2 (109 mg, yield 65%).

[0068] product 2 1 The H NMR nuclear magnetic data is as follows:

[0069] 1 H NMR(400MHz,DMSO-d6):δ0.83-0.88(t,6H),1.21-1.25(m,12H),1.41-1.50(m,4H),2.17-2.22(m,4H),6.39- 6.63 (m, 6H).

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Abstract

The invention discloses a cis-dammine dichloroplatinum (CDDP) prodrug, a preparation method and application. The structural formula of the CDDP prodrug is shown as formula (I), and is generated by theesterification reaction of activated dihydroxy cisplatin with hydrophobic molecules. Characterization of the nano-preparation by dynamic light scattering and transmission electron microscopy indicates that the nanoparticles involved in the invention are uniformly distributed and are at about 30nm. In vitro cytotoxicity experiments show that the nano-drug can significantly inhibit the proliferation of tumor cells (A549 and LoVo). In vivo experiments show that compared with CDDP injections, on the basis of reducing the systemic toxicity, the nano-drug has the effect of inhibiting the non-smallcell lung cancer A549 subcutaneous tumor, and has good market prospects and clinical application value.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and preparation, and specifically relates to a series of cisplatin drug prodrugs, their preparation method and application. Background technique [0002] Cis-diammine dichloroplatinum (cis-damminedichloroplatinum (II), cis-Pt (II) (NH 3 ) 2 Cl 2 , CDDP) is a heavy metal compound that is centered on divalent platinum and coordinated with two amino molecules and two chlorine atoms respectively. It was approved for clinical use by the U.S. Food and Drug Administration in 1978 ( Bristol-Myers Squibb). Its structural formula is as follows: [0003] [0004] As a clinical chemotherapy drug, CDDP is widely used in the treatment of osteosarcoma, soft tissue tumors such as testicular cancer, ovarian cancer, head and neck squamous cell carcinoma and lung cancer (Ana-Maria Florea and Dietrica Büsselbery, Cisplatinas an Anti-Tumor Drug: Cellular Mechanisms of Activity, Drug Resistance and Induce S...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F15/00A61K33/24A61K47/54A61K47/10A61P35/00
CPCA61K33/24A61K47/10A61K47/543A61P35/00C07F15/0093
Inventor 王杭祥
Owner ZHEJIANG UNIV
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