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Camptothecin prodrug, and preparation method and application thereof

A kind of technology of camptothecin and prodrug, applied in the field of small molecule amphiphilic drugs and preparation thereof

Active Publication Date: 2017-07-14
YANTAI LANNACHENG BIOTECHNOLOGY CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there is no such amphiphilic small molecule prodrug reported at home and abroad

Method used

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  • Camptothecin prodrug, and preparation method and application thereof
  • Camptothecin prodrug, and preparation method and application thereof
  • Camptothecin prodrug, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0093] Embodiment 1: the preparation of CPT-ss-OH

[0094] Under stirring, a solution of 4-dimethylaminopyridine (1.05 g, 8.60 mmol) in 10 mL of dichloromethane was added dropwise to a solution of camptothecin (1.0 g, 2.87 mmol) and triphosgene (0.315 g, 1.06 mmol). The mixture was suspended in anhydrous dichloromethane (200 mL). After stirring for 30 minutes, 2,2'-dithiodiethanol (8.60 g, 55.8 mmol) in anhydrous tetrahydrofuran (25 mL) was added and the reaction mixture was stirred at room temperature overnight. The mixture was washed with 50 mM aqueous hydrochloric acid (2×100 mL), water (1×100 mL) and saturated brine (1×100 mL). The organic layer was separated and dried over anhydrous sodium sulfate. The solution was concentrated by rotary evaporator and purified by flash chromatography using a prepacked silica column. Yield: 1.05 g (69% yield). 1 H NMR (300MHz, CD 2 Cl 2 )δ8.46(s, 1H), 8.22(d, J=8.3Hz, 1H), 7.99(dd, J=8.2, 1.1Hz, 1H), 7.86(ddd, J=6.9, 6.5Hz, 1H), 7....

Embodiment 2

[0095] Embodiment 2: Preparation of CPT-ss-COOH

[0096] Succinic anhydride (400 mg, 4.00 mmol), CPT-ss-OH (204 mg, 0.386 mmol) prepared in Example 1 and 4-dimethylaminopyridine (19.6 mg, 0.161 mmol) were dissolved in anhydrous dichloromethane under stirring (200mL). The reaction mixture was stirred at room temperature overnight, then washed with water (1×100 mL), 50 mM aqueous hydrochloric acid (1×100 mL) and saturated brine (1×100 mL). The organic layer was separated and dried over anhydrous sodium sulfate. The solution was concentrated by rotary evaporator and purified by flash chromatography using a prepacked silica column. Yield: 201 mg (83% yield). 1 H NMR (300MHz, CDCl 3 )δ8.44(s, 1H), 8.32(d, J=8.4Hz, 1H), 7.95(d, J=8.2Hz, 1H) (ddd, J=8.5, 6.9, 1.4Hz, 1H), 7.69( ddd, J=8.1, 7.0, 1.1Hz, 1H), 7.43(s, 1H), 5.71(d, J=17.3Hz, 1H), 5.39(d, J=17.3Hz, 1H), 5.32(s, 2H) , 4.46-4.25 (m, 4H), 3.00-2.86 (m, 4H), 2.79-2.61 m, 2H), 2.18 (m, J=2H), 1.01 (t, J=7.5, 3H). ESI-MS m...

Embodiment 3

[0097] Embodiment 3: Preparation of CPT-ss-EB

[0098] CPT-ss-COOH (58mg, 0.092mmol), EB-amine (25mg, 0.046mmol) prepared in Example 2, benzotriazol-1-yl-oxytripyrrolidinylphosphonium hexafluorophosphate (PyBOP, 48mg , 0.092mmol) and N,N-diisopropylethylamine (DIPEA, 59mg, 0.46mmol) were mixed in dimethylformamide and stirred under nitrogen for 2 days. The reaction was quenched by adding excess acetic acid and purified by preparative high performance liquid phase using acetonitrile and 0.2% acetic acid in water (gradient: 5-95% acetonitrile). The collected purified product was lyophilized and stored at -20°C for later use. Yield: 21 mg (40% yield). ESI-MS m / z: Calculated 1152, found 1151 (M-H). 1 H NMR (300MHz, DMSO) δ9.34(s, 1H), 8.70(d, J=3.7Hz, 1H), 8.35(s, 1H), 8.21-8.10(m, 3H), 8.02(d, 9.9Hz , 1H), 7.88 (dt, J=8.4, 4.1Hz, 2H), 7.73 (dd, J=6.9, 4.1Hz, 1H), 7.64 (dd, J=4.0Hz, J=6.5Hz, 1H), 7.50 (d, J=5.2Hz, 2H), 7.09(d, J=2.2Hz, 1H), 7.00(d, J=10Hz, 1H), 5.56-5.32(m, 4...

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Abstract

The invention provides a camptothecin prodrug. The camptothecin prodrug is a prodrug formed bycamptothecin or a derivative thereof and Evans blue, the structural formula of the prodrug is represented by formula (I); and in the formula, R<1> is camptothecin or a derivative group thereof, R<2> is one of -CH2- and -O-, R<3> is one of -CH2-, -O-CO- and -O-CO-NH-, X is one of S and -CH2-, and n1 and n2 are the repeating unit number, and are integers in a range of 0-10. The camptothecin prodrug has an excellent tumor cell uptake effect in vivo and in vitro, and a part of the prodrug has a substantial cancer cell inhibition effect. The invention also provides a preparation method of the camptothecin prodrug and an application of the camptothecin prodrug in the preparation of cancer treatment drugs.

Description

technical field [0001] The invention belongs to the technical field of drug controlled release, and in particular relates to a small-molecule amphiphilic drug formed by camptothecins and Evans blue and its preparation method and application. Background technique [0002] Cancer is one of the leading causes of morbidity and death worldwide. According to the World Health Organization, there were about 14 million new cases worldwide in 2012, and the number of new cases is expected to increase by about 70% in the next two decades. Cancer is the second leading cause of death worldwide, killing 8.8 million people in 2015. Globally, nearly one in six deaths is due to cancer, with approximately 70% of cancer deaths occurring in low- and middle-income countries. Currently, chemotherapy is one of the main treatments for cancer. However, most chemotherapeutic drugs, such as camptothecin, paclitaxel, and doxorubicin, have low solubility in water and have adverse side effects. For ex...

Claims

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Application Information

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IPC IPC(8): C07D491/22A61P35/00B82Y30/00
CPCB82Y30/00C07D491/22
Inventor 陈小元张福武
Owner YANTAI LANNACHENG BIOTECHNOLOGY CO LTD
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