Tumor-targeting lipophilic positive ion-chlorambucil compound and preparation method and application to albumin nano-drug

A tumor-targeting, chlorambucil technology, applied in the field of biomedicine, can solve the problems of low selectivity and multi-drug resistance of anti-cancer drugs, and achieve the advantages of drug delivery, prolonged in vivo imaging, and enhanced fluorescence. Effect

Active Publication Date: 2017-01-11
HUNAN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] Another object of the present invention is to provide the application of the above-mentioned tumor-targeting lipophilic cation-chlorambucil compound in the albumin nano drug system; the compound treats cancer with the mitochondria as the target, and overcomes the low selectivity of anticancer drugs and multi-drug resistance and inactivation, to achieve the effect of clearing cancer cells through apoptosis

Method used

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  • Tumor-targeting lipophilic positive ion-chlorambucil compound and preparation method and application to albumin nano-drug
  • Tumor-targeting lipophilic positive ion-chlorambucil compound and preparation method and application to albumin nano-drug
  • Tumor-targeting lipophilic positive ion-chlorambucil compound and preparation method and application to albumin nano-drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] First of all, take compound 1 trophylline with compound 2 pyridinecarbaldehyde The reaction gives compound 3, the structure of which is shown below:

[0052]

[0053] During the specific implementation, in the reaction bottle, add agrophylline (about 1.8g, 10.0mmol), pyridine formaldehyde (2.0eq), tributylphosphine (2.0eq) and anhydrous acetonitrile 50ml, then heat and reflux at 60°C overnight . After the reaction is complete, cool the reaction system to room temperature, remove the organic solvent under reduced pressure, concentrate to obtain an oil, and pass through a silica gel chromatography column (n-hexane / ethyl acetate, the volume ratio is (1~4):1, preferably 1:1) After purification, 1.9 g of compound 3 was obtained.

[0054] Next, add compound 3 (1.0g, 4.5mmol), 3-bromopropylamine hydrobromide in the reaction flask (1.0eq), 10ml of anhydrous methanol (or anhydrous ethanol, anhydrous ether), and then heated and refluxed overnight; the reaction was compl...

Embodiment 2

[0067] The method for preparing compound 3 is the same as that in Example 1, and will not be repeated here.

[0068] Take compound 3 to react with compound 10,

[0069]

[0070] Add compound 3 (1.0g, 4.5mmol), compound 10 (1.0eq), anhydrous methanol (or absolute ethanol, anhydrous ether) 10ml in the reaction flask, then heat and reflux to react overnight; the reaction is complete, and the reaction system is cooled to Room temperature, filtered, washed with a small amount of methanol, and dried to obtain light red semi-solid compound 11 (1.37g); in this example, the structure of compound 11 is as follows:

[0071]

[0072] Next, add compound 11 (1.0g, 2.5mmol), 20ml of tetrahydrofuran, 20ml of anhydrous sodium carbonate (2.0eq) in water, stir at room temperature for 30min, and then add di-tert-butyl dicarbonate (1.1eq) dropwise Dissolve in 10ml of tetrahydrofuran, react at 25-30°C for 6 hours; filter, spin the filtrate to dryness, then add 30ml of dichloromethane and met...

Embodiment 3

[0080] Example 3: Preparation and identification of conjugated compound albumin nanomedicine

[0081] For the coupling compounds 9 (F3CBL) and 15 (F6CBL) prepared in the foregoing Example 1 and Example 2, they were dissolved in a small amount of DMSO, and then dropped into the stirred human serum albumin phosphate buffer (pH: 7.4, the protein concentration is 0.5-20 mg / ml), stirred at 4-10°C for 10-120 min at low temperature, dialyzed in PBS overnight in a dialysis bag (molecular weight > 8000), and the albumin nanomedicine coupled with compound 9 or 15 can be obtained.

[0082] The albumin nano-medicines of compounds 9 and 15 and human serum albumin (HSA) were subjected to dynamic light scattering (Dynamic Light Scattering) DLS to measure the hydrated particle size of albumin particles in nanometer size. From the DLS analysis results, The hydrated particle sizes of compounds 8 and 14 are about 105nm and 120nm, and the dispersibility is good, and the PDI value is figure 2 . ...

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Abstract

The invention belongs to the field of biomedicine and discloses a tumor-targeting lipophilic positive ion-chlorambucil compound and a preparation method and application to an albumin nano-drug. The compound is of the structure shown in the formula (I), wherein Y is F, Cl, Br or I, and n is 0 or a natural number between 1 and 10. Cancer cell mitochondria serve as therapeutic targets of the compound and the albumin nano-drug of the compound, targeted cancer therapy is achieved, the problems of poor anti-cancer drug selectivity and multi-drug resistance are solved, and the cancer cell clearance effect is achieved in a cell apoptosis or death induction mode. Please see the formula in the description.

Description

technical field [0001] The invention belongs to the field of biomedicine, and in particular relates to a tumor-targeting lipophilic cationic (F)-chlorambucil compound, a preparation method and an application in albumin nano-medicine. Background technique [0002] Cancer is a chronic disease that seriously endangers human health, and has become the second largest killer after cardiovascular disease. Therefore, it is of great significance to find anti-tumor drugs and study their mechanism of action. [0003] Mitochondria are important organelles in cells and play an important role in cell metabolism. They are the "energy factory" of living organisms and participate in various metabolic processes such as energy-generating cell apoptosis and cell canceration. Changes in mitochondrial structure and function will not only interfere with cell growth, metabolism and proliferation, but also cause apoptosis. Therefore, the research and development of new anti-tumor drugs targeting mi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/06A61K31/4439A61K47/42A61P35/02C09K11/06
CPCA61K31/4439A61K47/42C07D401/06C09K11/06C09K2211/1029
Inventor 谭蔚泓彭咏波刘腾赵子龙张晓兵王若文
Owner HUNAN UNIV
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