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Camptothecin-polycaprolactone coupling prodrug, preparation method thereof, preparation, and preparation method and application of preparation

A technology of polycaprolactone and camptothecin, which is applied in preparation and its preparation, and in the field of camptothecin-polycaprolactone coupling prodrugs, can solve the problems of patients with drug diarrhea and severe gastrointestinal side effects, and achieve Good biocompatibility, good clinical application prospects, and low immunogenicity

Active Publication Date: 2021-04-16
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In addition, many clinical examples show that CPT-11 has serious gastrointestinal side effects, leading to drug diarrhea in patients

Method used

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  • Camptothecin-polycaprolactone coupling prodrug, preparation method thereof, preparation, and preparation method and application of preparation
  • Camptothecin-polycaprolactone coupling prodrug, preparation method thereof, preparation, and preparation method and application of preparation
  • Camptothecin-polycaprolactone coupling prodrug, preparation method thereof, preparation, and preparation method and application of preparation

Examples

Experimental program
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Effect test

preparation example Construction

[0073] mPCL 14 -C 2 -COOH is prepared as follows: Synthesis

[0074] Step 1: mPCL 14 synthesis

[0075]

[0076] To a solution of triethylene glycol monomethyl ether (0.931 g, 1.0 eqv.) and ε-caprolactone (9.069 g, 14.0 eqv.) in anhydrous toluene (50 ml) was added a catalytic amount of Sn(Oct) 2 . The mixture was stirred overnight at 150° C. for ring-opening reaction. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was dissolved in DCM and precipitated with cold ether. Filtrate under reduced pressure, and dry the solid in vacuum to obtain a white powder hydroxyl-terminated oligomer 14 (mPCL 14 ) (8.821 g, 88%).

[0077] Step 2: mPCL 14 -C 2 -COOH synthesis

[0078]

[0079] To a solution of hydroxyl terminated oligomer 14 (8.021 g, 1.0 eqv.) and succinic anhydride (2.279 g, 5.0 eqv.) in dry DCM (30 ml) was added dry pyridine (1.440 g, 4.0 eqv.). The mixture was heated to reflux for five days, followed by 5% ...

Embodiment 1

[0081] Example 1 mPCL 2 -C 2 - Synthesis of pSN38 coupled prodrug 1, as figure 1 Shown:

[0082] Add 7-ethyl-10-hydroxycamptothecin (SN38, 200.0mg, 0.5097mmol), mPCL in sequence to a 100mL round bottom flask equipped with a spherical condenser 2 -C 2 -COOH (250.9mg, 0.5097mmol, structure as figure 1 shown), and DMAP (74.8mg, 0.6116mmol), dissolved in 10mL of anhydrous dichloromethane, and then quickly dropwise added DISC (N,N'-diisopropylcarbodiimide) (193.1mg, 1.5291mmol) . Stir at 46°C overnight, and observe the reaction by thin-layer chromatography (developing solvent: DCM:MeOH=15:1). When the reaction was basically completed, the reaction liquid was cooled, and then washed with distilled water, 5% citric acid, saturated sodium carbonate, and saturated saline respectively. The organic layer was dried over anhydrous sodium sulfate, and filtered after complete drying. The filtrate was rotary evaporated to remove the solvent. Separation and purification by column chro...

Embodiment 2

[0083] Example 2 mPCL 7 -C 2 - Synthesis of pSN38 coupled prodrug 2, as figure 1 Shown:

[0084]Add 7-ethyl-10-hydroxycamptothecin (SN38, 300.0mg, 0.7645mmol), mPoCl 7 -C 2 -COOH (812.1mg, 0.7645mmol) and DMAP (112.1mg, 0.9174mmol) were dissolved in 10mL of anhydrous dichloromethane, and DISC (289.4mg, 2.2936mmol) was quickly added dropwise. Stir at 46°C overnight, and observe the reaction by thin-layer chromatography (developing solvent: DCM:MeOH=15:1). When the reaction was basically completed, the reaction liquid was cooled, and then washed with distilled water, 5% citric acid, saturated sodium carbonate, and saturated saline respectively. The organic layer was dried over anhydrous sodium sulfate, and filtered after complete drying. The filtrate was rotary evaporated to remove the solvent. Separation and purification by column chromatography (DCM:MeOH=60:1) to obtain the final product 2 (corresponding figure 2 The structure of n=7, 683.9 mg, yield 61.5%)

[0085] ...

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Abstract

The invention discloses a camptothecin-polycaprolactone coupling prodrug, a preparation method thereof, a preparation, and a preparation method and application of the preparation. According to the invention, the camptothecin polycaprolactone coupling prodrug is obtained by esterification of a camptothecin drug and polycaprolactone. According to the invention, polycaprolactone is covalently coupled with camptothecin or 7-ethyl-10-hydroxycamptothecine, so that the release rate of camptothecine active molecules in vivo can be regulated and controlled, the camptothecine active molecules are prevented from being separated out due to burst release, and the circulation time of the camptothecine active molecules in vivo is prolonged. Meanwhile, polycaprolactone is approved to be used in the market by FDA in America, and has a good application prospect. The camptothecin-polycaprolactone prodrug and an auxiliary agent are assembled to form nanoparticles, the nanoparticles have a passive targeting effect, and can be retained at a tumor site through an EPR effect to reduce exposure to normal tissues, so that the anti-tumor effect of the drug is greatly improved, and the in-vivo side effects are reduced.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a camptothecin-polycaprolactone coupling prodrug, a preparation, a preparation method and application thereof. Background technique [0002] 7-Ethyl-10-hydroxycamptothecin (SN38) is a camptothecin-like antitumor active molecule with broad-spectrum antitumor activity. It forms a ternary complex by combining with DNA and topoisomerase I , so as to effectively block the cell cycle and inhibit the proliferation of tumor cells. However, its poor water solubility (<2μg / mL) and low oral bioavailability make its clinical transformation extremely difficult. Irinotecan (CPT-11), as a water-soluble prodrug of SN38, has been used for colorectal cancer, lung cancer, cervical cancer, ovarian cancer, gastric cancer, etc. The treatment of malignant tumors, but its low enzymatic hydrolysis efficiency greatly limits the efficacy. CPT-11 can only be hydrolyzed into the acti...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/59A61K31/4745A61K47/69A61P35/00B82Y5/00
Inventor 王杭祥王雨晨
Owner ZHEJIANG UNIV
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