Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Camptothecin prodrug and application thereof

A technology of camptothecin and prodrug, applied in the field of preparing antitumor drugs, can solve the problems of increasing resistance, reducing therapeutic effect, low activity and the like

Pending Publication Date: 2022-01-25
LIAOCHENG UNIV
View PDF0 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The 20S-hydroxyl is connected to the carboxyl oxygen of Asp533 by a hydrogen bond. If it is a 20R-configured camptothecin, the steric hindrance of the ethyl group affects this interaction, so the activity is low.
Tumor cells in a hypoxic environment are prone to metastasis, and can increase resistance to radiotherapy and chemotherapy, thereby reducing the therapeutic effect

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Camptothecin prodrug and application thereof
  • Camptothecin prodrug and application thereof
  • Camptothecin prodrug and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0080] The camptothecin prodrug 4-ethyl-4-hydroxyl-9-((4-nitrobenzyl)oxy)-1,12-dihydro-14H-pyrano[3',4 ':6,7]indolizine[1,2-b]quinoline-3,14(4H)-dione (No. I-1) is synthesized by one-step reaction, and the reaction formula is as follows:

[0081]

[0082] Dissolve 0.5g (1.37mmol) of camptothecin in 20ml of N,N-dimethylformamide, add 0.38g (2.74mmol) of potassium carbonate, cool to 0°C, and protect with nitrogen. Slowly drop 0.30 g (1.37 mmol) of p-nitrobenzyl bromide dissolved in 5 mL of N,N-dimethylformamide with a syringe. After the addition, it was slowly raised to room temperature and reacted at room temperature for 12 hours. After the reaction, potassium carbonate was removed by filtration, and the filtrate was concentrated to obtain a crude product, which was separated by silica gel column chromatography and eluted with dichloromethane:methanol (20:1) to obtain 0.57 g of white solid (I-1), with a yield of 83.2%.

[0083] NMR characterization of I-1:

[0084] 1 H N...

Embodiment 2

[0087] The camptothecin class prodrug 4,11-diethyl-4-hydroxyl-9-((4-nitrobenzyl)oxy)-1,12-dihydro-14H-pyran[3 ',4': 6,7]indolizine[1,2-b]quinoline-3,14(4H)-dione (No. I-2) is synthesized by reaction, and the reaction formula is as follows:

[0088]

[0089] Dissolve 0.5g (1.27mmol) of hydroxycamptothecin in 20ml of N,N-dimethylformamide, add 0.35g (2.57mmol) of potassium carbonate, cool to 0°C, and protect with nitrogen. 0.28 g (1.27 mmol) of p-nitrobenzyl bromide dissolved in 5 mL of N,N-dimethylformamide was slowly dropped from a syringe. After the addition was completed, the temperature was slowly raised to 80° C., and the mixture was refluxed for 12 hours. After the reaction, potassium carbonate was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated by silica gel column chromatography and eluted with dichloromethane: methanol (2:1) to obtain 0.51 g of white solid (I-2), with a yield of 75.9 %....

Embodiment 3

[0094] Study on the degradation of camptothecin prodrugs mediated by tumor microenvironment (nitroreductase): Dissolve I-1 or I-2 in 15mL of 10mmol / L Tris buffer, add appropriate amount of nitroreductase and smoke Amide adenine dinucleotide or nicotinamide adenine dinucleotide phosphate, diluted to 20mL with 10mmol / L Tris buffer, measured by HPLC 100s, 200s, 300s, 400s, 500s after adding nitroreductase buffer , 600s... After the concentration of camptothecin and I-1 or hydroxycamptothecin and I-2, to determine whether the target compound can be degraded in the presence of nitroreductase. The results showed that compounds I-1 and I-2 could be degraded rapidly under the condition of nitroreductase.

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention provides a camptothecin prodrug and application thereof in preparation of antitumor drugs; wherein the camptothecin prodrug has the following general formula (I): MTT experiments show that the camptothecin prodrug has cytotoxicity only under the condition of nitroreductase and has low cytotoxicity in a culture solution without nitroreductase. Since concentration of nitroreductase in tumor tissue is high, anti-tumor drug prepared from camptothecin prodrug has characteristic of low toxicity.

Description

technical field [0001] The invention provides a novel camptothecin prodrug and the use of the prodrug in preparing antitumor drugs. [0002] technical background [0003] Malignant tumors are one of the common diseases that threaten human health, and the mortality rate of tumors ranks at the forefront of various diseases. The toxicity and side effects of anti-tumor drugs currently used in clinical practice are prominent problems in tumor chemotherapy. Improving the efficacy of tumor therapy while reducing drug toxicity is an important research topic for current tumor drugs. [0004] Camptothecin (CPT) and hydroxycamptothecin (hydroxycamptothecin) are alkaloids isolated from camptotheca acuminata, a plant endemic to my country. Camptothecin is composed of five rings A, B, C, D, and E. The A and B rings are quinoline rings, the C ring is a pyrrole ring, the D ring is a pyridone ring, and the E ring is a six-membered α-hydroxy internal ring. In the ester ring, the carbon atom...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
IPC IPC(8): C07D491/22A61K31/4745A61K9/00A61P35/00
CPCC07D491/22A61K9/0019A61K9/0053A61P35/00
Inventor 王学堃张昕萌郝慧然王世本雷康籍国霞冀芦沙柳仁民
Owner LIAOCHENG UNIV
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com