Camptothecin-adriamycin prodrug and preparation method and application thereof

A camptothecin and doxorubicin technology, which is applied in the field of camptothecin-doxorubicin prodrugs, can solve the problems of low drug loading, complex synthesis, and not the best curative effect of high molecular polymers

Active Publication Date: 2017-06-13
YANTAI LANNACHENG BIOTECHNOLOGY CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, it is difficult for them to be released from the polymer, and the release speed will not be consistent, resulting in not the best curative effect
Moreover, the drug-loading capacity of polymers is low and the synthesis is complex, so it is necessary to invent new methods that can deliver camptothecin and doxorubicin together simply and effectively.

Method used

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  • Camptothecin-adriamycin prodrug and preparation method and application thereof
  • Camptothecin-adriamycin prodrug and preparation method and application thereof
  • Camptothecin-adriamycin prodrug and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0070] Embodiment 1: the preparation of CPT-ss-OH

[0071] 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

[0072] Embodiment 2: Preparation of CPT-ss-LG

[0073] Under stirring, 4-nitrophenyl chloroformate (372mg, 1.85mmol), CPT-ss-OH (100mg, 0.184mmol) prepared in Example 1 and triethylamine (TEA, 224mg, 2.22mmol) were dissolved in water DCM, the reaction mixture was stirred at room temperature overnight, then purified by flash chromatography (Teledyne ISCO CombiFlash) using a prepacked silica column. A gradient mixture of ethyl acetate and hexane was used as eluent. Yield: 102 mg (80% yield). 1 H NMR (300MHz, CDCl 3 )δ8.40(s, 1H), 8.27-8.16(m, 3H), 8.12(d, J=9.0Hz, 1H), 7.94(d, J=8.0Hz, (t, J=7.3Hz, 1H) , 7.67(t, J=7.5Hz, 1H), 7.34(d, J=10.2Hz, J=17.2Hz, 1H), 5.43-5.32(m, 1H), 5.29(s, 2H), 4.55-4.41( m, 2H), 4.42-4.31 2H, 1H), 2.95 (td, J = 13.9, 6.3 Hz, 4H), 2.35-2.09 (m, 2H), 1.00 (t, J = 7.3 Hz, 3H). figure 2 for CPT-ss-LG 1 The H NMR spectrum proves that the compound was successfully prepared.

Embodiment 3

[0074] Embodiment 3: Preparation of CPT-ss-DOX

[0075] CPT-ss-LG (43 mg, 0.062 mmol), DOX.HCl (38 mg, 0.066 mmol), TEA (63 mg, 0.62 mmol) prepared in Example 2 were mixed in 3 mL of DMF and stirred under nitrogen for 1 day. The reaction was quenched by the addition of excess acetic acid and purified by preparative HPLC using acetonitrile and 0.1% trifluoroacetic acid in water (gradient: 20-95% acetonitrile). The collected purified product was lyophilized and stored at -20°C for later use. Yield: 35 mg (51% yield). 1 H NMR (300MHz, CDCl 3)δ8.36(s, 1H), 8.20(d, J=8.3Hz, 1H), 8.04(d, J=7.0Hz, 1H), 7.92(d, J=7.7, 1H), 7.86-7.73(m , 3H), 7.71-7.58(m, 2H), 7.43-7.36(m, 1H), 7.33(s, 1H), 5.70(d, J=17.2Hz, 2H) 2H), 5.45-5.14(m, 7H ), 4.77(d, J=4.3Hz, 2H), 4.66(s, 1H), 4.37(s, 2H), 4.18-4.01(s, 2H), 3.65(s, 2H), 3.32(s, 1H) , 3.26(s, 1H), 3.07(s, 1H), 3.01(s, 1H), 2.89(d, J=2H), 2.81(dd, J=10.7, 6.2Hz, 2H), 2.43-2.09(m , 7H), 2.02-1.75 (m, 5H), 1.36-1.25 (m, 10H), 1.02 (t, 7.5Hz...

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Abstract

The invention provides camptothecin-adriamycin prodrug. A structural formula of the prodrug is shown as a formula (I), wherein R1 is camptothecin or derivative group thereof, R2 is one of -CH2- or -O-, R3 is one of -CH2- or -O-, X is one of S or -CH2-, and n1 and n2 are numbers of repeated units, and are integers from 0 to 10. The prodrug can be easily wrapped by amphiphilic polymer to form nanoparticles. The nanoparticles are high in drug carrying efficiency and drug carrying capacity and capable of quickly releasing unmodified camptothecin and adriamycin in the presence of glutathione, and the nanoparticles can be effectively taken in by tumor cells to kill the same. The invention further provides a preparation method of the prodrug, a preparation of the prodrug and application of the prodrug in preparing cancer treating drug.

Description

technical field [0001] The invention relates to the technical fields of biomedicine technology, nanometer medicine and drug controlled release, in particular to a camptothecin-doxorubicin prodrug of a reducing and degrading drug, and a preparation method and application thereof. Background technique [0002] Cancer is the second leading cause of death worldwide. According to the World Health Organization, cancer killed 8.8 million people in 2015. Nearly one in six deaths worldwide 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 chemotherapy drugs, such as camptothecin, paclitaxel, etc., have limited solubility in water and have adverse side effects. Therefore, the modification of chemotherapy drugs and the design of effective drug delivery systems have always been the focus of research in the field of controlled drug release. Nanomedici...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/22A61K31/4375A61P35/00A61K9/51
CPCA61K9/5146A61K31/4375C07D491/22
Inventor 陈小元张福武
Owner YANTAI LANNACHENG BIOTECHNOLOGY CO LTD
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