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Vitamin A acyl cytosine arabinoside conjugate and pharmacome thereof as well as preparation methods and application thereof

A technology of retinyl cytarabine and said formyl arabinoside, which is applied in the field of biomedicine, can solve the problems of low encapsulation rate, no amphiphilicity, easy leakage and the like, and achieves the effect of protection and inactivation

Inactive Publication Date: 2009-12-09
CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These drug delivery systems have some common problems: ①The dosage is difficult to control
② Low encapsulation efficiency, easy leakage, and unstable drug loading
All-trans retinoic acid has the characteristics of strong fat solubility and poor water solubility. On the contrary, cytarabine has strong water solubility but poor fat solubility. Defects such as inability to self-assemble into drug plasmids need to be improved

Method used

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  • Vitamin A acyl cytosine arabinoside conjugate and pharmacome thereof as well as preparation methods and application thereof
  • Vitamin A acyl cytosine arabinoside conjugate and pharmacome thereof as well as preparation methods and application thereof
  • Vitamin A acyl cytosine arabinoside conjugate and pharmacome thereof as well as preparation methods and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Example 1, Preparation of Retinoyl Cytarabine Conjugate

[0026] Dissolve 0.6g (2mmol) ATRA (all-trans retinoic acid), 0.454g (2.2mmol) DCC (dicyclohexylcarbodiimide) and 0.270g (2mmol) HOBT (1-hydroxybenzotriazole) in Add 0.558g (2mmol) HCl·Ara-C (cytarabine hydrochloride) to an appropriate amount of anhydrous pyridine solution under the conditions of protecting from light and Ar gas, and then add 0.558g (2mmol) of HCl Ara-C (cytarabine hydrochloride) after stirring in an ice bath for 20 minutes. Protected, stirred at room temperature for 2 days, TLC (chloroform / methanol, 10:1) showed that the points of ATRA and Ara-C became shallower, the reaction solution was spin-dried under reduced pressure, added an appropriate amount of chloroform to dissolve, and filtered out DCU (dicyclohexyl urea ), the filtrate was spin-dried under reduced pressure, the residue was washed with excess ether, the ether was removed by rotary evaporation under reduced pressure, the residue was di...

Embodiment 2

[0027] The preparation of embodiment 2 retinoyl cytarabine drug plasmid

[0028] Weigh the retinoyl cytarabine conjugate prepared in Example 1 into an eggplant-shaped bottle, add an appropriate amount of lecithin and fully dissolve it with chloroform, place it on a rotary evaporator, and remove the solvent by rotary evaporation in a constant temperature water bath at 35°C until A layer of gel film appears on the wall of the bottle, add phosphate buffer, then vibrate by hand or on a vortex mixer until all or part of the film falls off, sonicate in a water bath for 20 minutes, and the target compound can be dissolved in phosphate buffer with the help of lecithin A uniform dispersion system is formed in the liquid, with no particles by visual inspection, and light blue scattered light. Under the optical microscope, some uniform small particles can be seen swimming, and it is preliminarily determined that a vesicle-shaped drug substance is obtained. Through the measurement of the...

experiment example 1

[0029] Experimental example 1 Inhibitory effect of retinoyl cytarabine conjugates on the proliferation of human leukemia cells HL-60

[0030] Test compound: retinoyl cytarabine conjugate (ATRA-Ara-C) prepared in Example 1;

[0031] Human leukemia cell line HL-60 was regularly subcultured with RPMI1640 culture medium (containing 10% inactivated fetal bovine serum, penicillin 100u / ml, streptomycin 100ug / ml).

[0032] Drug preparation: the positive control is all-trans retinoic acid (ATRA), cytarabine (Ara-C) and the physical mixture of all-trans retinoic acid and cytarabine (ATRA+Ara-C) dissolved in 1 ‰ ethanol in PBS phosphate buffered saline made 5 x 10 -6 mol / L concentration solution, the test compound was dissolved in 1‰ ethanol PBS phosphate buffer solution to make a solution with the same amount concentration as the positive control group. Dilute to 8×10 before use -9 mol / L, 4×10 -8 mol / L, 2×10 -7 mol / L, 1×10 -6 mol / L, 5×10 -6 mol / L five concentrations. The negativ...

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Abstract

The invention discloses a vitamin A acyl cytosine arabinoside conjugate with amphipathic and a pharmacome formed by the conjugate. The invention also discloses preparation methods and the application as the antitumor agent of the conjugate and the pharmacome. The invention enables RA and cytosine arabinoside 4'-amido to be coupled so as to obtain the vitamin A acyl cytosine arabinoside conjugate with amphipathic, and the conjugate has the characteristic of self assembly of the pharmacome, thereby not only protecting the cytosine arabinoside 4'-amido from devitalizing, but also enabling the conjugate and prepared pharmacome to have the tumor targeting ability. The invention respectively takes human leukaemia cells HL-60 and S180 ascites carcinoma mousse to value the antineoplastic activity of a compound of formula I and the pharmacome prepared by the compound in vivo and in vitro, and test results show that the compound of formula I and the pharmacome thereof have excellent antineoplastic activity.

Description

technical field [0001] The present invention relates to compounds with anti-tumor activity, especially retinoyl cytarabine conjugates with anti-tumor activity and drug plastids constructed from the retinoyl cytarabine conjugates. The present invention Also disclosed are their preparation methods and their application in antitumor, belonging to the field of biomedicine. Background technique [0002] Many drugs need to cross the biomembrane multiple times in the body to reach the target site (organ, tissue, cell and organelle). Among the many factors affecting drug transmembrane, hydrophilic-lipophilic balance or oil-water partition coefficient are obvious physical and chemical factors. Strongly water-soluble drugs are compatible with body fluids and cannot easily pass through biological membranes composed of lipid bilayers. Although highly fat-soluble drugs can easily enter the lipid bilayer, they are incompatible with body fluids and difficult to transport in body fluids, ...

Claims

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Application Information

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IPC IPC(8): C07H19/09A61K31/7068A61P35/00
Inventor 崔国辉崔纯莹张云玮
Owner CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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