Podophyllotoxin phospholipid compound as well as pharmaceutical composition and application of podophyllotoxin phospholipid compound

A technology of phospholipid compound and podophyllotoxin, which is applied in the field of medicine, can solve the problems of leakage of drugs and difficulty in exerting efficacy of drugs, and achieve the effect of low toxicity and side effects.

Inactive Publication Date: 2015-11-11
SOUTHEAST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the fluidity of the liposome membrane, the drug is easy to leak out, making it difficult for the encapsulated drug to exert a good drug effect

Method used

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  • Podophyllotoxin phospholipid compound as well as pharmaceutical composition and application of podophyllotoxin phospholipid compound
  • Podophyllotoxin phospholipid compound as well as pharmaceutical composition and application of podophyllotoxin phospholipid compound
  • Podophyllotoxin phospholipid compound as well as pharmaceutical composition and application of podophyllotoxin phospholipid compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0112] Synthesis of bis(podophyllotoxin-4-succinic acid) phosphatidylcholine (see the synthetic route figure 1 )

[0113] Podophyllotoxin 0.5g, succinic anhydride 3g, DMAP 0.1g, triethylamine 3g, add dichloromethane as reaction solvent, reflux reaction for 12h; wash with dilute hydrochloric acid three times, filter dilute hydrochloric acid layer, take filter cake; add methanol to dissolve, Place at 4°C for 12 hours, filter, take the filter cake, and dry to obtain the intermediate product podophyllotoxin-4-succinic acid monoester.

[0114] Podophyllotoxin-4-succinic acid monoester 0.6g, add CDI1.2g, dichloromethane is reaction solvent, add GPC0.4g and DBU1g to react at room temperature, the obtained reaction solution is purified by column chromatography, and the product bis(podophyllotoxin - 4-succinic acid) phosphatidylcholine (MW1249.4) 0.28g.

[0115] For the NMR spectrum of the compound, see figure 2 , 1 HNMR (500MHz, (CD 3 ) 2 SO): δ6.86(2H,s,8-H),6.56(2H,s,5-H),6.4...

Embodiment 2

[0118] Synthesis of bis(4'-desmethyl epipodophyllotoxin-4-succinic acid) phosphatidylcholine (see the synthetic route Figure 4 )

[0119] 0.5g of 4'-desmethyl epipodophyllotoxin, 3g of succinic anhydride, 0.1g of DMAP, 3g of triethylamine, add dichloromethane as the reaction solvent, react at 45°C for 48h; wash with dilute hydrochloric acid three times, filter the dilute hydrochloric acid layer, Take the filter cake; add methanol to dissolve, place at 4°C for 12h, filter, take the filter cake, and dry to obtain the intermediate product 4'-desmethyl epipodophyllotoxin-4-succinic acid monoester.

[0120] Add 0.5g of 4'-desmethyl epipodophyllotoxin-4-succinic acid monoester, add 1.0g of CDI, dichloromethane as the reaction solvent, add 0.3g of GPC and 0.8g of DBU to react at room temperature, and the resulting reaction solution is passed through column chromatography After purification, 0.24 g of the product bis(4'-desmethylepipodophyllotoxin-4-succinic acid) phosphatidylcholine ...

Embodiment 3

[0124] Synthesis of bis(podophyllotoxin-4-succinic acid) phosphatidylethanolamine (see the synthetic route Figure 5 )

[0125] Take 0.5g of 3-(4-methoxybenzyloxy)propane-1,2-diol, 0.5g of succinic anhydride, 0.1g of DMAP, 0.5g of triethylamine, add dichloromethane as the reaction solvent, add reflux React, react for 12 hours; wash with dilute hydrochloric acid three times, filter the dilute hydrochloric acid layer, and take the filter cake; add 0.5g of CDI, add dichloromethane as the reaction solvent, and react at room temperature for 3h; add 0.5g of podophyllotoxin, DBU0.5g, and react at room temperature 12h, spin dry the solvent; add dilute acetic acid, react at room temperature for 6h, remove the solvent; add phosphorus oxychloride 0.5g, triethylamine 0.5g, add dichloromethane as the reaction solvent, react at 10°C for 24h, spin dry the solvent; Add 0.5 g of aminoethanol, 0.3 g of triethylamine, add dichloromethane as the reaction solvent, react at 10°C for 24 hours, and ...

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Abstract

The invention discloses a podophyllotoxin phospholipid compound as well as a pharmaceutical composition and application of the podophyllotoxin phospholipid compound. The pharmaceutical composition comprises a podophyllotoxin phospholipid compound or a combined pharmaceutical composition of the podophyllotoxin phospholipid compound and a pharmacologically-acceptable carrier and is a liquid preparation, a solid preparation, a semi-solid preparation, a capsule, granules, gel and an injection. The pharmaceutical composition is a liposome nanoparticle (with the particle size of 10-1000nm) prepared from the podophyllotoxin phospholipid compound or the podophyllotoxin phospholipid compound and an adjuvant. The podophyllotoxin phospholipid compound and the liposome nanoparticle thereof can be used as liquid preparations, solid preparations, semi-solid preparations, disinfection preparations and sterile preparations, are low in toxicity and can be used for efficiently treating tumors.

Description

technical field [0001] The invention relates to a podophyllotoxin phospholipid compound with antitumor effect, its pharmaceutical composition and application, and relates to the technical field of medicine. Background technique [0002] Podophyllotoxin (podophyllotoxin), also known as podophyllin and podophyllotoxin, is an anti-tumor natural lignan compound isolated from plants of the genus Podophyllum. It has various biological activities such as anti-tumor, anti-virus and anti-inflammatory. Among them, the remarkable antitumor activity is the most proud advantage of this kind of compound. As early as 1942, Kaplan confirmed that podophyllotoxin had an inhibitory effect on tumor growth, and then King and Sullivna pointed out that podophyllotoxin inhibited tumor growth by preventing the formation of microtubule bundles in the metaphase of cell mitosis. [0003] Podophyllotoxin has significant antitumor activity, but its side effects are relatively large, especially the toxi...

Claims

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Application Information

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IPC IPC(8): C07F9/6561A61K31/683A61K31/685A61P35/00
Inventor 李新松凌龙兵方硕何瑞玉
Owner SOUTHEAST UNIV
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