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Camptothecin derivative and applications thereof

A technology of camptothecin and its derivatives is applied in the field of preparing anti-tumor drugs, which can solve the problems of lack of tumor tissue targeting, low activity, and large toxic and side effects.

Inactive Publication Date: 2020-04-17
LIAOCHENG UNIV
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  • 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.
However, because the current camptothecin derivatives lack tumor tissue targeting, the toxicity and side effects are relatively large.

Method used

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  • Camptothecin derivative and applications thereof
  • Camptothecin derivative and applications thereof
  • Camptothecin derivative and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] The camptothecin derivative of this example 4,11-diethyl-4-hydroxy-9-((4-(4,4,5,5-tetramethyl-1,3,2-oxopentaboron Alkyl-2-)phenyl)oxy)-1H-pyrano[3',4':6,7]indolazine[1,2-b]quinoline-3,14(4H,12H)-dione (No. SN-1) is synthesized through a one-step reaction, and the reaction formula is as follows.

[0063]

[0064] Dissolve 0.5 g (2.13 mmol) of 4-(hydroxymethyl) phenylboronic acid pinacol ester in 25 ml of dichloromethane, cool to 0°C, and protect with nitrogen. A solution of 0.2 ml (2.13 mmol) of phosphorus tribromide dissolved in 2 ml of dichloromethane was slowly added dropwise with a syringe, and the reaction was quenched by adding water for 0.5 h. After adding 25ml of dichloromethane, washed twice with 50ml of saturated sodium bicarbonate and 50ml of saturated sodium chloride solution respectively, retaining the organic phase, adding anhydrous sodium sulfate to dry, suction filtration and rotary evaporation to obtain 4-(bromomethyl) Pinacol phenylboronic acid est...

Embodiment 2

[0069]Tumor microenvironment (ROS)-mediated degradation of prodrugs: target compounds were dissolved in TE buffer (100uM), and 0.1mM H was added at 37°C 2 O 2 (or HO or HOCl) or buffer, add H by HPLC 2 O 2 Or the concentration of the target compound after 100s, 200s, 300s, 400s, 500s, 600s... of the buffer to determine whether the target compound can be degraded in the presence of ROS. The results showed that compound SN-1 could be slowly degraded under ROS conditions.

Embodiment 3

[0071] Cytotoxicity test: collect the log phase cells of HeLa cell line, adjust the concentration of cell suspension, add 100ul to each well, and plate the cells to adjust the density to 1000-10000 wells (the edge wells are filled with sterile PBS); 5% CO 2 , incubate at 37°C until the cell monolayer covers the bottom of the well (96-well flat bottom plate), add the drug with concentration gradient, set 5-7 concentration gradients, 5 duplicate wells, 100ul per well; 5% CO 2 , incubated at 37°C for 24h, and observed under an inverted microscope; 20ul MTT solution (5mg / ml, ie 0.5% MTT) was added to each well, and the culture was continued for 4h. If the drug can react with MTT, the culture medium can be discarded after centrifugation. Carefully rinse with PBS for 2-3 times, and then add the MTT-containing culture medium. The culture was terminated, and the culture medium in the well was carefully aspirated; 150 ul of dimethyl sulfoxide was added to each well, and it was shaken a...

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Abstract

The invention provides a camptothecin derivative and applications in preparation of antitumor drugs, wherein the camptothecin derivative has the following general formula (I). According to the invention, the MTT experiment results show that the camptothecin derivative has cytotoxicity only under ROS conditions, and has low cytotoxicity in a ROS-free culture solution; and based on high ROS concentration in tumor tissue, the anti-tumor medicine prepared from the camptothecin derivative has the advantage of low toxicity.

Description

technical field [0001] The invention provides a novel camptothecin derivative and use of the derivative in the preparation of antitumor drugs. [0002] technical background [0003] Malignant tumor is one of the common diseases that threaten human health, and tumor mortality ranks first among all diseases. The toxicity of anti-tumor drugs currently used in clinical practice is a prominent problem that plagues tumor chemotherapy. Improving the therapeutic effect of tumor while reducing drug toxicity is an important research topic of current tumor drugs. [0004] Camptothecin (CPT) and hydroxycamptothecin (hydroxycamptothecin) are alkaloids isolated from Camptotheca (Cam ptotheca acuminata) 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, and the E ring is a six-membered α-hydroxy Ester ring, the carbon atom at the 20th position of the hydroxyl group...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F5/02A61K31/69A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07F5/025
Inventor 王学堃范雪静张紫馨孙孟超徐兆敏王世本雷康柳仁民
Owner LIAOCHENG UNIV
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