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Camptothecin phospholipid compound, drug composition and application thereof

A technology of phospholipid compound and camptothecin, which is applied in the field of medicine, can solve the problems of slow drug release, difficulty in reaching effective drug concentration, disappearance of anti-tumor activity, etc., and achieve the effect of low toxicity and side effects

Active Publication Date: 2015-12-09
SOUTHEAST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, chemically modifying the 20-hydroxyl group or failing to quickly release the 20-position hydroxyl group after chemical modification will lead to the disappearance or decline of anti-tumor activity
Studies have shown that the esterification of the 20-hydroxyl group of camptothecin compounds results in no inhibitory activity to DNA topoisomerase I (Topoisomerase I) (Hert

Method used

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  • Camptothecin phospholipid compound, drug composition and application thereof
  • Camptothecin phospholipid compound, drug composition and application thereof
  • Camptothecin phospholipid compound, drug composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0122] Synthesis of two (hydroxycamptothecin-10-dithiodiacetic acid) phosphatidylcholine compounds (see the synthetic route figure 1 )

[0123] Dissolve 1g of 10-hydroxycamptothecin and 2g of dithiodiacetic anhydride in 30mL of pyridine, react at 40°C for 48h; remove the solvent by rotary evaporation, precipitate in cold ether, wash with dilute hydrochloric acid, and obtain the intermediate product hydroxycamptothecin-10 - Dithiodiacetate monoester 0.81 g.

[0124] Dissolve 0.8g of the intermediate product hydroxycamptothecin-10-dithiodiacetic acid monoester in 20mLDMSO, add 0.6g of CDI, activate for 1h, add 0.4g of GPC and 0.6g of DBU, react at room temperature for 24h, and the resulting reaction solution is passed through column chromatography After purification, 0.56 g of the product bis(hydroxycamptothecin-10-dithiodiacetic acid) phosphatidylcholine compound was obtained.

[0125] 1 HNMR (500MHz, CD 3 OD: CDCl 3 1:1): δ8.07-7.43 (8H, m), 6.74 (2H, s), 6.51 (2H, s), 4....

Embodiment 2

[0127] Synthesis of bis(hydroxycamptothecin-10-diglycolic acid) phosphatidylcholine compound (see the synthetic route figure 2 )

[0128] Dissolve 1g of 10-hydroxycamptothecin and 3g of diglycolic anhydride in 30mL of pyridine, react at 40°C for 48h; remove the solvent by rotary evaporation, precipitate in cold ether, wash with dilute hydrochloric acid, and obtain the intermediate product hydroxycamptothecin-10-di Glycolic acid monoester 0.85g. Take 0.8g of the intermediate product hydroxycamptothecin-10-diglycolic acid monoester, dissolve it in 20mL of DMSO, add 0.8g of CDI, activate for 1h, add 0.4g of GPC and 0.8g of DBU, react at room temperature for 24h, and the resulting reaction solution passes through the column layer Analysis and purification yielded 0.51 g of the product bis(hydroxycamptothecin-10-diglycolic acid) phosphatidylcholine compound.

[0129] 1 HNMR (500MHz, CD 3 OD: CDCl 3 1:1): δ8.07-7.43 (8H, m), 6.74 (2H, s), 6.51 (2H, s), 4.75 (4H, s), 4.64-3.77 ...

Embodiment 3

[0131] Synthesis of bis(hydroxycamptothecin-10-succinyl-glycyl)phosphatidylcholine compound (synthetic route see image 3 )

[0132] Dissolve 1g of 10-hydroxycamptothecin and 1.5g of succinic anhydride in 30mL of pyridine, react at 40°C for 48h; remove the solvent by rotary evaporation, precipitate in cold ether, wash with dilute hydrochloric acid, and obtain the intermediate product hydroxycamptothecin-10-succinic acid Monoester 0.75g. Dissolve 0.7 g of the intermediate product hydroxycamptothecin-10-succinic acid monoester in 20 mL of DMF, add 0.5 g of CDI and 0.5 g of TEA, activate for 1 h, then add 1.0 g of glycine, react at room temperature for 24 h, and separate the reaction solution by column chromatography to obtain hydroxycamptothecin Dentin-10-succinyl-glycine 0.53 g. The above product was dissolved in 10 mL of dimethyl sulfoxide, added CDI0.6g, activated for 1h, added GPC0.25g and DBU0.6g, reacted at room temperature for 24h, precipitated in cold ether, separated ...

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Abstract

The invention discloses a camptothecin phospholipid compound, a preparation method, a drug composition and application thereof. The drug composition is a camptothecin phospholipid compound or a medical composition combining the camptothecin phospholipid compound with a carrier that is acceptable in pharmacodynamics, can be taken as a liquid preparation, solid preparation, semisolid preparation, capsules, granules, gel or injection; the drug composition is the camptothecin phospholipid compound or lipidosome nano-particles prepared from the camptothecin phospholipid compound and an assistant, the grain size of the drug composition is 10-1000 nanometers; the camptothecin phospholipid compound or the camptothecin phospholipid compound lipidosome can quickly release active camptothecin phospholipid compound crude drugs, thereby having a strong anti-tumor effect; the camptothecin phospholipid compound and lipidosome nano particles of the compound can be used as a liquid preparation, solid preparation, semisolid preparation, sterilization preparation and sterile preparation, are low in toxicity, and can be used for efficiently treating various tumors.

Description

technical field [0001] The invention relates to a camptothecin-like phospholipid compound with antitumor effect, its pharmaceutical composition and application, and relates to the technical field of medicine. Background technique [0002] Camptothecin (CPT) and 10-hydroxycamptothecin (HCPT) are alkaloids extracted from the seeds or root bark of Camptothecin, a deciduous plant of the Davidiaceae family, and have strong cytotoxic activity. It is used to treat a variety of malignant tumors, such as gastric cancer, liver cancer, bladder cancer and leukemia. The chemical structure of 10-hydroxycamptothecin is similar to that of camptothecin (CPT), only the hydrogen on the 10th carbon atom is replaced by hydroxyl (-OH), which is a natural derivative of CPT. [0003] Scientists have discovered the unique anti-cancer mechanism of camptothecin compounds: by forming a stable triplet complex of camptothecin-topoisomerase I-DNA, the DNA double helix structure cannot be replicated after...

Claims

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Application Information

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IPC IPC(8): C07F9/6561A61K31/675A61P35/00
Inventor 李新松张伟杜亚伟
Owner SOUTHEAST UNIV
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