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Camptothecin prodrug monomer and polymeric prodrug amphipathic molecules thereof as well as preparation method and application of camptothecin prodrug monomer and polymeric prodrug amphipathic molecules

A technology of amphiphilic molecules and camptothecin, which is applied in the field of medicinal chemistry and biodegradable medical polymers, can solve the problems of lack of tumor microenvironment response release characteristics and limited drug loading, and achieve improved water solubility and stable stability. The effect of controlled release

Active Publication Date: 2014-01-22
UNIV OF SCI & TECH OF CHINA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Recently, CN103251596 discloses the preparation of an amphiphilic polymer prodrug of a camptothecin derivative 7-ethyl-10-hydroxycamptothecin, but the amphiphilic polymer prodrug does not have tumor microenvironmental response Release profile with limited drug loading (less than 40%)

Method used

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  • Camptothecin prodrug monomer and polymeric prodrug amphipathic molecules thereof as well as preparation method and application of camptothecin prodrug monomer and polymeric prodrug amphipathic molecules
  • Camptothecin prodrug monomer and polymeric prodrug amphipathic molecules thereof as well as preparation method and application of camptothecin prodrug monomer and polymeric prodrug amphipathic molecules
  • Camptothecin prodrug monomer and polymeric prodrug amphipathic molecules thereof as well as preparation method and application of camptothecin prodrug monomer and polymeric prodrug amphipathic molecules

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0078] Example 1: Single-ended modification of hydroxyethyl disulfide

[0079] As shown in Scheme 1, in a 500mL round bottom flask, weigh hydroxyethyl disulfide (6.16g, 40mmol), triethylamine (6.07g, 60mmol) and 200mL of dry THF, cool in an ice-water bath and stir with a magnet Under certain conditions, methacryloyl chloride (4.18 g, 40 mmol, in 100 mL THF) was slowly added dropwise, and after the dropwise addition was completed, it was stirred overnight at room temperature. The triethylamine hydrochloride by-product generated by the reaction was removed by filtration, and the filtrate was collected to remove the solvent by rotary evaporation, then dissolved in ethyl acetate, washed with water and saturated NaCl aqueous solution three times, and the organic phase was collected and dried with anhydrous magnesium sulfate, then filtered, concentrate. The crude product was separated and purified by silica gel column chromatography, and eluted with ethyl acetate:petroleum ether=1:...

Embodiment 2

[0080] Example 2: Preparation of Reductively Responsive Camptothecin Prodrug Monomer CPTM

[0081]According to the above scheme 1, dissolve and disperse CPT (2.0g, 5.74mmol) and DMAP (2.11g, 17.3mmol) in 50mL of dry dichloromethane, add triphosgene (0.567g, 1.92mmol), react at room temperature for 30min, and then add dropwise A solution of the above product (Formula 2) in dry THF (1.40 g, 6.31 mmol in 15 mL THF) was contained. A white precipitate formed after overnight reaction. After filtration, the filtrate was collected, concentrated, dissolved in ethyl acetate, washed with water and saturated NaCl aqueous solution three times, and the organic phase was collected and dried over anhydrous magnesium sulfate. The crude product was separated and purified by silica gel column chromatography, and eluted with ethyl acetate to obtain a light gray solid powder (2.92 g, yield: 86%). figure 1 (b) shows the hydrogen spectrum of the CPTM prepared in this example: 1 H NMR (CDCl 3 , δ...

Embodiment 3

[0082] Embodiment 3: Polyethylene glycol monomethyl ether end group RAFT modification

[0083] According to the above scheme 2, polyethylene glycol monomethyl ether (PEG 45 -OH, 4.0g, 2.0mmol) was dissolved in anhydrous toluene (25mL), and most of the solvent was removed by azeotroping under reduced pressure at 50°C, then the small molecule RAFT reagent (1.09g, 4.0mmol) of formula 3 was added and dried dichloromethane (100mL), cooled to 0°C in an ice-water bath, dicyclohexylcarbodiimide (0.83g, 4.0mmol) and N,N-dimethylaminopyridine (49mg, 0.4mmol) were added dropwise in dichloromethane mixture. Stir the reaction at room temperature for 48 hours, remove the generated by-product salt by filtration, concentrate under reduced pressure, precipitate in excess anhydrous ether, filter and dry, dissolve dichloromethane and then precipitate with anhydrous ether. The compound of formula 4 can be obtained by repeating three times. figure 2 shows the polyethylene glycol monomethyl eth...

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Abstract

The invention relates to a reduced response camptothecin prodrug monomer as shown in a formula I, reduced response camptothecin polymeric prodrug amphipathic molecules of the reduced response camptothecin prodrug monomer, and a preparation method and application of the reduced response camptothecin prodrug monomer and the reduced response camptothecin polymeric prodrug amphipathic molecules. In the formula I, each i is 2 or 3 independently, each X is O or NH independently, and R is H, CH3 or CH2CH3. According to the preparation method, raw materials including camptothecin, triphosgene and the like are used for modifying 20 bits of hydroxyls of camptothecin to prepare a camptothecin prodrug monomer containing disulfide bonds, then the camptothecin prodrug monomer is subjected to high-conversion-rate polymerization by using active free radical polymerization method to obtain an amphiphilic polymer which contains a camptothecin drug repetitive unit and has an extremely high drug loading capacity (more than 50wt%), and in a tumor cell reducing environment, a side chain disulfide bond is broken to perform molecular rearrangement and release camptothecin prodrug molecules, so that the amphiphilic polymer has characteristics of a reduced response controlled-release raw drug. The polymeric prodrug amphipathic molecules improve the water solubility and stability of the drug and have a controlled release characteristic.

Description

technical field [0001] The invention relates to the fields of medicinal chemistry and biodegradable medical polymers, more specifically to camptothecin prodrug monomers and polymerized prodrug amphiphilic molecules, and their preparation methods. Background technique [0002] Camptothecin (CPT) is an alkaloid extracted from Camptotheca japonica in China, and its molecular formula is: C 20 h 16 o 4 , the molecular weight is: 348.11, CAS.NO.7689-03-4, and its molecular structure is shown in the following formula c: [0003] [0004] It has strong anti-tumor activity, and its mechanism of action can be simply described as: lactone-type active camptothecin can bond with topoisomerase and DNA to form a covalent complex, thereby stabilizing DNA and topoisomerase. This bonding method eventually leads to cell apoptosis. Since the solubility of camptothecin in water is extremely poor, and the lactone ring structure is also easy to open to inactivate the drug, it is of great si...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/22C08G65/48C08F120/38C08F120/60C08F2/38A61K47/48A61K31/4745A61P35/00A61K47/60
CPCA61K47/60C07D491/22C08F2/38C08F120/38C08F120/60C08F2438/01C08G65/48C08G2650/04
Inventor 刘世勇胡祥龙
Owner UNIV OF SCI & TECH OF CHINA
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