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Clathrate compound of camptothecin and acid-sensitive open-loop cucurbituril

An acid-sensitive, cucurbituril technology, which is applied in the field of targeted preparations of camptothecin drugs, can solve the problems of cyclodextrin inclusion without targeting and cumbersome derivatization process, and overcome low bioavailability and water solubility. The effect of poor performance and simple preparation method

Inactive Publication Date: 2019-05-14
KUNMING UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These camptothecin derivatives and inclusion complexes increase the water solubility of camptothecin to a certain extent, but the derivatization process is cumbersome, and cyclodextrin inclusion has no targeting

Method used

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  • Clathrate compound of camptothecin and acid-sensitive open-loop cucurbituril
  • Clathrate compound of camptothecin and acid-sensitive open-loop cucurbituril
  • Clathrate compound of camptothecin and acid-sensitive open-loop cucurbituril

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Example 1: The inclusion compound of camptothecin and acid-sensitive split-loop cucurbituril contains camptothecin and acid-sensitive split-loop cucurbituril (a), and the structural formula of acid-sensitive split-loop cucurbituril is as follows:

[0028] , R 1 =CH 3 , R 2 =H or R 1 = H, R 2 = H;

[0029] Camptothecin and acid-sensitive secocucurbituril (a, R 1 =CH 3 , R 2 = H; R 1 = H, R 2 =H) Preparation of clathrates

[0030] (1) 0.1 mmol acid-sensitive split-ring cucurbituril (a, R 1 =CH 3 , R 2 =H) into the ethanol solution, add 0.1mmol camptothecin, continue to stir in the dark for 24 hours, use a 4.5μm microporous membrane filter to remove insoluble matter, evaporate the solvent under reduced pressure, and obtain camptothecin and acid-sensitive split cucurbita Urea (a, R 1 =CH 3 , R 2 =H) powdery solid clathrate; from figure 1 , image 3 It can be seen that camptothecin and acid-sensitive secocucurbituril (a, R 1 =CH 3 , R 2 =H) The clathr...

Embodiment 2

[0037] Example 2: The inclusion compound of camptothecin and acid-sensitive split-loop cucurbituril contains camptothecin and acid-sensitive split-loop cucurbituril (b), wherein the structural formula of acid-sensitive split-loop cucurbituril is as follows:

[0038] ;

[0039] Camptothecin and acid-sensitive secocucurbituril (b, R 1 =CH 3 , R 2 = H; R 1 = H, R 2 =H) Preparation of clathrate

[0040] (1) 0.1 mmol acid-sensitive split-ring cucurbituril (b, R 1 =CH 3 , R 2 =H) into the ethanol solution, add 0.3mmol camptothecin, continue to stir in the dark for 48 hours, use a 4.5μm microporous membrane filter to remove insoluble matter, evaporate the solvent under reduced pressure, and obtain camptothecin and acid-sensitive split-ring cucurbit Urea (b, R 1 =CH 3 , R 2 =H) powdery solid clathrate;

[0041] (2) 0.1 mmol of acid-sensitive split-ring cucurbituril (b, R 1 = H, R 2 =H) into the ethanol solution, add 0.4mmol camptothecin, continue to stir in the dark fo...

Embodiment 3

[0047] Example 3: The inclusion compound of camptothecin and acid-sensitive split-loop cucurbituril contains camptothecin and acid-sensitive split-loop cucurbituril (c), wherein the structural formula of acid-sensitive split-loop cucurbituril is as follows:

[0048] ;

[0049] Camptothecin and acid-sensitive secocucurbituril (c, R 1 = H, R 2 =CH 3 ; 1 = H, R 2 =H) Preparation of clathrate

[0050] (1) 0.1 mmol acid-sensitive open-loop cucurbituril (R 1 = H, R 2 =CH 3 ) in ethanol solution, add 0.5mmol camptothecin, continue to avoid light and stir for 72h, use 4.5μm microporous membrane filter to remove insoluble matter, evaporate the solvent under reduced pressure, and obtain camptothecin drug and acid-sensitive split-ring cucurbituril (c, R 1 =CH 3 , R 2 =H) powdery solid clathrate;

[0051] (2) 0.1 mmol of acid-sensitive open-loop cucurbituril (c, R 1 = H, R 2 =H) into the ethanol solution, add 0.3mmol camptothecin, continue to stir in the dark for 84 hours,...

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Abstract

The invention discloses a clathrate compound of camptothecin and acid-sensitive open-loop cucurbituril. The clathrate compound comprises camptothecin and acid-sensitive open-loop cucurbituril, and themolar ratio of camptothecin to acid-sensitive open-loop cucurbituril is 1:1 to 5:1. According to the clathrate compound, open-loop cucurbituril has a C-shaped cavity and can wrap the drug camptothecinv to form the clathrate compound, due to the fact that open-loop cucurbituril belongs to flexible molecules, the size of the cavity can be changed according to the size of the drug, and therefore open-loop cucurbituril and the drug form good cavity matching, and then the water solubility of camptothecin is enhanced to improve the bioavailability of camptothecin. The clathrate compound can fast release the drug in the cavity fast in the exterior tumor environment (weak acid condition), and therefore targeted release of the drug is achieved. The prepared clathrate compound is good in water solubility and high in stability and has potential value on development of clinical application of camptothecin.

Description

technical field [0001] The invention belongs to the technical field of pharmacy and pharmaceutical preparations, and in particular relates to targeted preparations of camptothecin drugs. Background technique [0002] Camptothecin (CPT) is a quinoline alkaloid with cytotoxicity and anticancer activity extracted from the plant camptotheca by M.E. Wall et al. in 1966. Its mechanism of action is to combine with DNA topoisomerase (Topo I) and destroy DNA strands in the S phase and G2 / M phase of the cell cycle (ie, during DNA replication). Natural camptothecin has poor water solubility, high toxicity and side effects, and short retention time in the body, resulting in low antitumor activity. In addition, the active form of camptothecin lactone is prone to ring-opening reaction and converted to a biologically inactive form (carboxylate) under physiological pH or alkaline conditions, thus limiting the clinical application of camptothecin. The Chinese patent whose publication numbe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/69A61K31/4745A61P35/00
Inventor 杨波林洁玲李凡结赵榆林廖霞俐高传柱
Owner KUNMING UNIV OF SCI & TECH
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