no n -Application of acyl amino acid ester in the preparation of antitumor drugs

A technology of acyl aminoester and anti-tumor drugs, applied in the field of anti-tumor drugs and drugs, to achieve the effects of high encapsulation efficiency, good biocompatibility and high safety

Active Publication Date: 2022-01-21
CENT SOUTH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, using the principle of prodrugs, although the early release of drugs can be avoided to a certain extent, as mentioned above, after the drugs are released from cancer cells or pathogens to play a role, the free drugs may also act on normal cells through diffusion and other mechanisms. Cells thus bring toxicity, and such toxicity cannot be solved by using the principle of prodrugs

Method used

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  • no <sup>n</sup> -Application of acyl amino acid ester in the preparation of antitumor drugs
  • no <sup>n</sup> -Application of acyl amino acid ester in the preparation of antitumor drugs
  • no <sup>n</sup> -Application of acyl amino acid ester in the preparation of antitumor drugs

Examples

Experimental program
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Effect test

preparation example

[0042] Preparation example: the synthetic method of AKE (formula 1-A):

[0043] (1) Esterification reaction

[0044] Will N α -Benzyloxycarbonyllysine (N α -Cbz-lys, the lysine whose α-amino group is protected by benzyloxycarbonyl) and the corresponding alcohol (R2-OH) (per 1mmol N α -Cbz-lys, add 3-10ml R2-OH), stir and cool in -10℃ ethanol bath for 10-30min, add thionyl chloride dropwise (every 1mmol N α -Cbz-lys was added with 5-7 mmol thionyl chloride), and stirring was continued at room temperature for 20 h. Evaporate under reduced pressure to remove excess thionyl chloride, methanol and HCl generated in the reaction until a white solid is obtained, which is dried in vacuo at 50°C to obtain the esterification reaction product N α -Benzyloxycarbonyl lysine ester (N α -Cbz-lysine ester).

[0045] (2) Acylation reaction

[0046] The last step esterification reaction product N α -Cbz-lysine ester, ethyl acetate and triethylamine (add 20-30ml of methanol and 3-4mmol of...

Embodiment 1

[0052] Embodiment 1 liposome preparation method

[0053] The preparation method of the folic acid modified targeted liposome (FA-PEG-AKE-LP) of the medicine of the present invention:

[0054]Prepared by conventional film hydration method, soybean lecithin (SPC), drug AKE (MKM was specifically used in this case), polyethylene glycol 2000-distearoylphosphatidylethanolamine (PEG2000-DSPE), folic acid-polyethylene Diol 2000-distearoylphosphatidylethanolamine (FA-PEG2000-DSPE) is added into the eggplant-shaped bottle at a molar ratio of 60:20:5:0.5, and fully dissolved with 50-100 times (w / w) methanol , use a rotary evaporator to evaporate under reduced pressure in a 45°C water bath to form a thin film in the bottle, and then use a vacuum pump to completely remove methanol. Then add 50-100 times (w / w) 0.01M pH7.4 phosphate buffered saline solution (PBS) to the eggplant-shaped bottle, use a rotary evaporator to hydrate in a water bath at 45°C for 30 minutes to obtain a milky white ...

Embodiment 2

[0057] Drug encapsulation efficiency and drug loading stability test of embodiment 2 liposome

[0058] Drug Encapsulation Efficiency Determination After the drug-loaded liposome stock solution is prepared, take a sample in an ultrafiltration tube (30KD), centrifuge for 10min under 12000g centrifugal force with a desktop high-speed centrifuge, and obtain the centrifugate with a high-performance liquid chromatography (HPLC). Analyze free drug concentration. By comparing with the dosage, the drug encapsulation efficiency can be calculated. Results The encapsulation efficiency of the drug AKE of the present invention in the drug-loaded liposome (prepared in Example 1) was 92.6%-93.7%, indicating that the encapsulation efficiency of the drug in the liposome was relatively high (over 90%).

[0059] Drug-loaded stability test After the drug-loaded liposome stock solution is prepared, it is diluted with 0.01M PBS with pH 7.4 and complete cell culture medium containing serum to a conc...

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Abstract

The invention belongs to the field of chemotherapeutic drugs and specifically discloses a N n The application of acyl amino acid ester in the preparation of antineoplastic drugs. and discloses a modification with the N n ‑Acyl Amino Acid Esters Antineoplastic Drugs. The present invention found for the first time, N n ‑Acyl amino acid ester has good anticancer activity and anticancer selectivity, can effectively promote the rupture and death of cancer cells, and can avoid the impact on normal cells, with little toxic and side effects. In addition, the anti-cancer active chemotherapeutic component of formula 1 described in the present invention is easy to synthesize and obtain, and the cost is low.

Description

technical field [0001] The invention belongs to the field of medicines, in particular to the field of antitumor medicines. Background technique [0002] Due to lack of selectivity, chemotherapeutic drugs are also highly toxic to normal cells. Classical chemotherapeutic drugs including anticancer drugs, such as cisplatin, doxorubicin, amphotericin B, etc., will all cause systemic toxic and side effects without exception; Although some natural chemotherapeutic drugs such as paclitaxel have good anticancer activity, they have complex structures and many chiral centers, which are mainly obtained by natural component extraction or semi-synthesis. At present, it is still impossible to rely on artificial total synthesis. The source of materials is effective and the cost is high. . [0003] Nano drug delivery system is a highly respected chemotherapy drug carrier in recent years, such as liposomes (LP), lipid or polymer vesicles, polymer micelles, organic or inorganic nanoparticles...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/223A61P35/00
CPCA61K31/223A61P35/00
Inventor 王艳彭坚吴条
Owner CENT SOUTH UNIV
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