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Amphiphilic prodrug of 7- ethyl-10-hydroxycamptothecin and preparation method thereof

A hydroxycamptothecin and amphiphilic technology, applied in the field of amphiphilic drug precursors and their preparation, can solve problems such as slow drug release, achieve high drug loading, improve stability, and overcome the problem of low drug loading. Effect

Inactive Publication Date: 2012-11-21
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In addition, Fumiaki Koizumi synthesized a block polymer of PEG and polyglutamic acid, and then linked SN38 to the polymer through a condensing agent; the polymer can form nanoparticles of tens of nanometers in water, and The drug loading capacity of the drug reached 20% (Koizumi, F. et al; Novel SN-38-Incorporating Polymeric Micelles, NK012, Eradicate Vascular Endothelial Growth Factor-Secreting Bulky Tumors; Cancer Res 2006, 66, 1004); but the It takes 24 hours for the compound to release half of its drug, which is not good for reaching cell-killing drug concentrations in time
It can be seen that the relatively stable chemical bonds release the drug slowly, and basically all bonds have this weakness

Method used

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  • Amphiphilic prodrug of 7- ethyl-10-hydroxycamptothecin and preparation method thereof
  • Amphiphilic prodrug of 7- ethyl-10-hydroxycamptothecin and preparation method thereof
  • Amphiphilic prodrug of 7- ethyl-10-hydroxycamptothecin and preparation method thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] The synthesis of the bond PEG-SN-38 (10) that the 10-position hydroxyl of embodiment 1PEG is connected with SN-38

[0054] (1) Synthesis of PEG-SH

[0055] Mix polyethylene glycol monomethyl ether acrylate (Mn=480, 10.8g) with ethanedithiol (10g), add 0.5ml triethylamine as a catalyst, stir overnight at room temperature, extract with water, and extract the water extract with After washing with n-hexane, the water was removed by rotary evaporation, and the 1H-NMR (400M, CDCl 3 ): δ(ppm) 4.06(t), 3.469(br), 3.450(t), 3.194(s), 2.599(m), 2.471(t), 1.604(t), indicating that the PEG with the structure shown in formula a was obtained -SH (8 g, 80% yield).

[0056] (2) Reaction of SN-38 and methacrylic anhydride

[0057] SN-38 (1g) and methacrylic anhydride (1ml) were added to 10ml of anhydrous pyridine, reacted for 5 hours, then introduced into petroleum ether for precipitation, and suction filtered to obtain the product (1.1g, yield 94%).

[0058] 1H-NMR (400MHz, CDCl 3...

Embodiment 2

[0065] The synthesis of the bond PEG-SN-38 (20) that the 20-position hydroxyl of embodiment 2PEG is connected with SN-38

[0066] (1) Protection of the 10-hydroxyl group of SN-38

[0067] Di-tert-butyl dicarbonate (Boc 2 O, 2 grams) and SN-38 (2 grams) were mixed in dichloromethane (100 milliliters), and excess pyridine (10 milliliters) was added as a catalyst, stirred until the system became clear, and then washed with 1 mol / liter of aqueous hydrochloric acid , dried over anhydrous sodium sulfate, and dried by rotary evaporation to obtain 3 g of the product, with a yield close to 100%.

[0068] product by 1 H-NMR (400MHz, CDCl 3 ) detection shows that it is a compound of structure shown in formula d.

[0069] (2) Acrylylation of the 20-position hydroxyl of the compound of structure shown in formula d

[0070] Add SN-38 with the 10-position hydroxyl protected and acryloyl chloride in anhydrous dichloromethane at a molar ratio of 1:1, use 2 times the molar amount of trieth...

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Abstract

The invention discloses an amphiphilic prodrug of 7- ethyl-10-hydroxycamptothecin, which is prepared by connecting hydroxyl at the site 10 and / or 20 site of the 7-ethyl-10- hydroxycamptothecin and a hydrophilic group through a scissionable chemical bond. The amphiphilic prodrug is self-assembled in water to form a micelle or vesicle structure. Therefore, on one hand, the solubility of SN-38 in water is greatly increased, and the stability of SN-38 lactone rings is improved; and on the other hand, the drug loading rate is high and the SN-38 can be quickly released in cells, consequently the defect of low drug loading rate of traditional drugs is overcame. Moreover, with the nano-micelles or the nano-vesicles of the prodrug, EPR (enhanced permeability and retention) effect targeted cancer tissues of tumors can be effectively utilized.

Description

technical field [0001] The invention relates to the field of amphiphilic drug prodrugs and the preparation thereof, in particular to an amphiphilic drug prodrug of 7-ethyl-10-hydroxycamptothecin and a preparation method thereof. Background technique [0002] 7-Ethyl-10-hydroxycamptothecin (SN-38 for short), is one of the important derivatives of camptothecin, and its molecular formula is C 22 h 20 N 2 o 5 , the molecular weight is 392.31, CAS.NO: 86639-52-3, the structural formula is as follows: [0003] [0004] SN-38 is one of the camptothecin anticancer drugs. In clinical practice, among camptothecin drugs, irinotecan and topotecan have been approved for use. These two types of drugs are obtained by modifying the functional groups of SN-38 and 10-hydroxycamptothecin respectively. Improved solubility of camptothecins in water. SN-38 is the active product obtained from the metabolism of irinotecan in the body. Its drug properties can reach 1000 times that of irinot...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C08G65/48C07D491/22A61K9/00A61K47/48A61P35/00A61K47/60
Inventor 申有青王金强唐建斌隋梅花
Owner ZHEJIANG UNIV
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