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Synthesis and applications of an albumin bounding type 5-fluorouracil prodrug

A technology of albumin-binding and fluorouracil, which is applied in drug combinations, medical preparations containing active ingredients, anti-tumor drugs, etc., to prolong the plasma half-life and improve anti-tumor activity

Active Publication Date: 2017-05-10
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There is no such 5-fluorouracil prodrug in the prior art and its design is applied to drug delivery system

Method used

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  • Synthesis and applications of an albumin bounding type 5-fluorouracil prodrug
  • Synthesis and applications of an albumin bounding type 5-fluorouracil prodrug
  • Synthesis and applications of an albumin bounding type 5-fluorouracil prodrug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Preparation of 6-maleimidocaproic acid and 1-(6-maleimidocaproyloxymethyl)-5-fluorouracil

[0036] (a) Dissolve 7.845g (80mmol) of maleic anhydride and 10.494g (80mmol) of 6-aminocaproic acid in 70mL of glacial acetic acid, reflux in an oil bath at 140°C for about 2.5h, spin to dry the solvent after the reaction, and remove the toluene with water (2×30mL), spin-dried and then extracted with ethyl acetate, the organic layers were combined and dried overnight with anhydrous sodium sulfate, spin-dried, separated and purified on a silica gel column to obtain the product (II).

[0037] (b) Take 4.215g (32.4mmol) of 5-fluorouracil, add 5.357mL (71.28mmol) of 37% formaldehyde solution, put in an oil bath at 55°C until the solid is completely dissolved, continue to react for about 4 hours, and spin dry to obtain a colorless transparent viscous liquid (Ⅲ). Another 5.699g (27mmol) of 6-maleimidocaproic acid, 7.421mL (67.5mmol) of N-methylmorpholine and 13.346g (35.1mmol) of HATU...

Embodiment 2

[0043] Binding of 1-(6-maleimidocaproyloxymethyl)-5-fluorouracil to bovine serum albumin in vitro

[0044] Weigh 1-(6-maleimidocaproyloxymethyl)-5-fluorouracil and dissolve it in pH 7.4 phosphate buffer solution to make the concentration 300 μM. Another bovine serum albumin with a mass of 46.2 mg was weighed, and 1 mL of 1-(6-maleimidocaproyloxymethyl)-5-fluorouracil solution was added, shaken slightly to dissolve, so that the concentration of bovine serum albumin 700 μM. The mixed solution was incubated in a constant temperature shaker at 37°C, samples were taken at 2, 5, 90 minutes and 6, 24 hours, and 10 μM samples were injected into high performance liquid chromatography.

[0045] In addition, a group of control experiments were carried out. First, the 34 free sulfhydryl groups of bovine serum albumin were fully blocked with excess 6-maleimidocaproic acid, and then mixed with 1-(6-maleimidocaproyl Oxymethyl)-5-fluorouracil was incubated for binding.

[0046] The results...

Embodiment 3

[0048] 5-fluorouracil release experiment of 1-(6-maleimidocaproyloxymethyl)-5-fluorouracil albumin complex in different pH phosphate buffer

[0049] The reaction conditions of the in vitro binding experiment were adopted, that is, 46.2 mg of bovine serum albumin was weighed and added to 1 mL of 1-(6-maleimidocaproyloxymethyl)-5-fluorouracil aqueous solution with a concentration of 300 μM at 37 ° C. Incubate under the conditions for 90 minutes, at this time, no free 1-(6-maleimidocaproyloxymethyl)-5-fluorouracil can be detected, that is, the reaction is complete. After lyophilization, 1-(6-maleimidocaproyloxymethyl)-5-fluorouracil albumin complex is obtained. Take a portion of the above freeze-dried sample, add it to 1 mL of phosphate buffer (pH 2.5, 7.4 and 10.5), transfer the solution to a dialysis bag, place in a conical flask containing 10 mL of the corresponding phosphate buffer, The hydrolysis experiments were carried out in a constant temperature shaker at 37°C. Draw 1...

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Abstract

The invention relates to an albumin bounding type 5-fluorouracil prodrug, and applications thereof in anti-tumor drug transfer. The prodrug is a compound formed by bridging 4-maleimidobutyric acid, 6-maleimidocaproic acid or 8-maleimido octanoic acid and N1-hydroxymethyl-5-fluorouracil through an ester bond, wherein the maleimido group is adopted as a bonding target of free sulfydryl of 34-site cysteine of albumin. The prodrug compound can be rapidly specifically bonded with albumin in blood to form an albumin prodrug composite, and therefore the drug metabolism speed is reduced, drug half life is significantly prolonged, and a long circulation function is achieved. In addition, under EPR effects and albumin acceptor mediation, tumor targeting is achieved and antitumor effects are improved. The 5-fluorouracil prodrug is used for intravenous injection and has a wide market application prospect.

Description

technical field [0001] The invention belongs to the field of prodrug design of pharmaceutical preparations, and relates to a 5-fluorouracil prodrug that rapidly and specifically combines with serum albumin after intravenous injection, significantly prolongs the half-life of 5-fluorouracil in vivo, and improves antitumor activity. preparation, and their use as prodrugs in drug delivery. Background technique [0002] As an antimetabolite, 5-fluorouracil is widely used in the clinical treatment of various solid tumors. However, 5-fluorouracil will be rapidly metabolized and degraded in the blood, and its plasma half-life is only 10-20 minutes. To address this dilemma, we designed 5-fluorouracil prodrugs that can rapidly bind to albumin in vivo. Albumin is the protein with the highest content in human blood, and albumin is widely used as an endogenous drug carrier to reduce the metabolic rate of drugs. In addition, it has been documented that malignant tumors can accumulate a...

Claims

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Application Information

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IPC IPC(8): C07D403/12A61K31/506A61P35/00
CPCC07D403/12
Inventor 孙进何仲贵赵东阳陶文慧
Owner SHENYANG PHARMA UNIVERSITY
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