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A kind of camptothecin-based heterodimer multifunctional prodrug and its preparation method and application

A technology of heterodimer and camptothecin is applied in the field of heterodimer multifunctional prodrugs to achieve the effects of reducing toxic and side effects, improving curative effect and being easy to prepare

Active Publication Date: 2019-12-10
SHANGHAI THERANOSTICS BIOTECH CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] At present, there is no such heterodimer multifunctional prodrug reported at home and abroad

Method used

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  • A kind of camptothecin-based heterodimer multifunctional prodrug and its preparation method and application
  • A kind of camptothecin-based heterodimer multifunctional prodrug and its preparation method and application
  • A kind of camptothecin-based heterodimer multifunctional prodrug and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] Embodiment 1: the preparation of CPT-ss-HPPH

[0068] DMAP (1.15 mg, 9.42 μmol), HPPH (30 mg, 4.71 μmol) and CPT-ss-OH (51.0 mg, 94.3 μmol) were mixed in 20 mL of dichloromethane. A solution of 5 mL of EDC HCl (18.1 mg, 94.3 μmol) in dichloromethane was added dropwise with stirring. After stirring at room temperature for 24 hours, complete reaction of HPPH was confirmed by thin layer chromatography (TLC). The mixture solution was concentrated using a rotary evaporator and then purified by flash chromatography (Teledyne ISCOCombiFlash) using a gradient of ethyl acetate and hexanes as eluents. Yield 39.9 mg (74%). ESI-MS m / z (M + )calcd 1146.46,found 1147.24(M+H + ). 1 H NMR (300MHz, CDCl 3 )δ9.80(d, J=8.9Hz, 1H), 9.52(s, 1H), 8.44(d, J=5.7Hz, 1H), 8.00(t, J=8.7Hz, 1H), 7.69–7.51( m,2H),7.42–7.28(m,2H),7.21(d,J=7.5Hz,1H),5.91(p,J=6.5Hz,1H),5.68(d,J=17.2Hz,1H), 5.38–5.3(m,1H),5.09(qd,J=20.0,3.0Hz,2H),4.81(d,J=6.0Hz,1H),4.69(dd,J=17.3,1.2Hz,1H),4.44 –4.38(m,1H),4.4...

Embodiment 2

[0070] Embodiment 2: Preparation of CPT-cc-HPPH

[0071]DMAP (0.58 mg, 4.75 μmol), HPPH (15 mg, 23.5) and CPT-cc-OH (23.8 mgmg, 47.1 μmol) were mixed in 20 mL of dichloromethane. A solution of 5 mL of EDC HCl (9.1 mg, 47.1 μmol) in dichloromethane was added dropwise with stirring. After stirring at room temperature for 24 hours, complete reaction of HPPH was confirmed by thin layer chromatography (TLC). The mixture solution was concentrated using a rotary evaporator and then purified by flash chromatography (Teledyne ISCOCombiFlash) using a gradient of ethyl acetate and hexanes as eluents. Yield: 22.5 mg (86%).ESI-MS m / z (M + )calcd 1110.55,found 1111.32(M+H + ). 1 H NMR (300MHz, CDCl 3 )δ9.78(d,J=4.1Hz,1H),9.52(s,2H),8.50(s,1H),8.19–7.95(m,4H),7.79–7.59(m,2H),7.57–7.45 (m,2H),7.27(s,2H),5.98–5.83(m,2H),5.68(d,J=17.3Hz,2H),5.37(dd,J=17.1,1.1Hz,2H),5.28( d,J=8.9Hz,1H),5.20(s,2H),5.17–5.02(m,3H),4.46(q,J=7.4Hz,1H),4.28(d,J=8.3Hz,1H), 4.11–3.98(m,2H),3.99–3.81(m,2H),3.79–...

Embodiment 3

[0073] Example 3: Generation of Reactive Oxygen Species (ROS) by HPPH and CPT-ss-HPPH

[0074] The ROS generation of HPPH and CPT-ss-HPPH prepared in Example 1 was measured by using anthracene-9,10-dipropionic acid (ADPA) as ROS quencher. Briefly, ADPA was dissolved in DMSO and diluted to have a UV-Vis absorbance of 1.1 at 410 nm. HPPH or CPT-ss-HPPH in 1 mM DMSO was then added to a final concentration of 10 μM. The obtained solution was irradiated with a 671 nm laser at an intensity of 100 mW for 7 minutes. At each minute, the UV-Vis absorbance of the solution was recorded by a UV3100PC spectrophotometer (VWR, Radnor, PA). The obtained results were analyzed by Origin 8.

[0075] Such as Image 6 As shown, we found that the absorbance of HPPH and CPT-ss-HPPH decreased continuously with the increase of irradiation time. Notably, the absorbance of CPT-ss-HPPH decreased faster than that of HPPH, indicating that CPT-ss-HPPH was able to generate more ROS ( Image 6 a-c). Fur...

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Abstract

The invention provides a heterodimer multifunctional prodrug based on camptothecin. The heterodimer multifunctional prodrug is loaded with the camptothecin and 2-(1-hexyloxy ethyl)-2-devinyl-pyropheophorbide-a (HPPH), the prodrug is a camptothecin-HPPH prodrug formed by the camptothecin and the HPPH through a connecting group, and the structural formula of the prodrug is as shown in formula (I), wherein R is the connecting group and is one of -SS-, -CH2CH2- or -S(CH3)C(CH3)S-; R1 is the camptothecin group. The prodrug has the advantages that the prodrug can be easily wrapped by amphiphilic polymer to form nano particles, and the formed nano particles are high in drug loading efficiency and drug loading capacity and can fast release the unmodified camptothecin and HPPH in the presence of glutathione; meanwhile, the nano particles can be effectively absorbed by tumor cells to kill the tumor cells. The invention further provides a preparation method and preparation of the prodrug and application of the prodrug in the preparation of drugs for treating cancer.

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-based heterodimer multifunctional prodrug of reductive degrading medicine, its preparation method and application. 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. ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D519/00A61K9/51A61K31/4745A61K41/00A61K47/55A61K49/00A61K51/04A61P35/00
CPCA61K9/5146A61K31/4745A61K41/0076A61K47/55A61K49/0036A61K51/0485A61P35/00C07D519/00A61K2300/00
Inventor 陈小元张福武
Owner SHANGHAI THERANOSTICS BIOTECH CO LTD
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