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Novel camptothecin derivative and application thereof to preparation of antitumor drug

An anti-tumor drug, camptothecin technology, applied in the direction of anti-tumor drugs, drug combinations, pharmaceutical formulations, etc., can solve the problems of poor water solubility, lack of targeting, poor stability, etc., to achieve reduced anti-tumor activity and strong anti-tumor Active, low toxicity effect

Inactive Publication Date: 2021-04-27
YANTAI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although many studies have shown that CPT has a good anti-tumor effect, there are still many problems that limit its clinical application: (1) Poor water solubility, it is almost impossible to take it orally
(2) poor stability
(3) Lack of targeting
Although there are a large number of literatures reporting a variety of novel camptothecins and some progress has been made, it is still extremely challenging to reduce their toxic side effects while maintaining their anti-tumor activity.

Method used

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  • Novel camptothecin derivative and application thereof to preparation of antitumor drug
  • Novel camptothecin derivative and application thereof to preparation of antitumor drug
  • Novel camptothecin derivative and application thereof to preparation of antitumor drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] The synthesis of embodiment 1 novel camptothecin derivative C

[0021] Prepare as follows:

[0022]

[0023] 1) Preparation of compound 7: Add compound 4 (5.42g, 22mmol), acetonitrile (108.4mL), succinic anhydride (2.0g, 20mmol) and 4-dimethylaminopyridine (3.7g, 30mmol) into a 1L flask, The reaction mixture was stirred overnight at room temperature. Concentrate first, then add ethyl acetate to dilute, wash with water, then dry the organic phase with anhydrous sodium sulfate, concentrate to dryness, and the obtained residue is separated by preparative HPLC to obtain compound 7 (2.1 g, 30.3% yield). LC-MS m / z: 347[M+H]+; RT=4.901min.

[0024] 2) Preparation of Compound C: Compound 1 (2.83 g, 7.22 mmol), 1-(3-di Methylaminopropyl)-3-ethylcarbodiimide (2.8 g, 14.4 mmol) and 4-dimethylaminopyridine (88 mg, 0.722 mmol). The reaction mixture was stirred overnight at room temperature. Concentrate first, then add ethyl acetate to dilute, wash with water, then dry the or...

Embodiment 2

[0025] Example 2 Inhibitory experiment of camptothecin derivative C on the proliferation of colorectal cancer LS180, HCT116, HT-29 and CT-26

[0026] The present invention adopts MTT method to study the proliferation inhibitory effect of camptothecin derivative C on colorectal cancer LS180, HCT116, HT-29 and CT-26.

[0027] LS180, HCT116, HT-29 and CT-26 cells were planted on 96-well plates at a density of 3×10 3 / well (100 μL), at 37°C, 5% CO 2 Cells were cultured overnight in an incubator. After 24 hours, the cells were treated with different concentrations of the tested compounds. For LS180 and CT-26 cells, camptothecin derivatives C, SN-38 and CPT-11 were prepared by diluting 10 μM stock solution with RPMI-1640 complete medium. The RPMI-1640 complete medium solution containing 0.1% DMSO was used as the control. For HCT116 and HT-29 cells, the compound was formulated using McCoys 5A complete medium diluted 10 μM stock solution, and McCoys 5A complete medium solution cont...

Embodiment 3

[0034] Embodiment 3 toxicity test

[0035] Human colorectal adenocarcinoma cell line LS180 was used to construct a xenograft tumor model to investigate the antitumor activity of camptothecin derivative C in vivo, and CPT-11 was used as a positive control.

[0036] Nude mice (8 weeks old, BALB / c, male) were used to establish xenograft tumors. LS180 cells (5x10 61) inoculated into the subcutaneous tissue of the right armpit, and injected 100 μL (PBS: Matrigel 1:1). When the tumor volume reaches 100-200mm 3 When left and right, mice were randomly divided into 3 groups, control group, camptothecin derivative C (10 mg / kg), CPT-11 (10 mg / kg), 7 mice in each group. Tumor size and mouse body weight were measured every 3 days. Animals were sacrificed 27 days after tumor cell implantation.

[0037] Test results such as figure 1 As shown: the inhibitory rate of camptothecin derivative C to tumor is greater than that of CPT-11, and the body weight of the animals in the camptothecin ...

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Abstract

The invention belongs to the field of organic synthesis, and discloses a novel camptothecin derivative and an application thereof to preparation of an antitumor drug. The toxicity of the novel camptothecin derivative is reduced on the premise of ensuring the stability and antitumor activity of the novel camptothecin derivative through structural modification, and an effective quantity of camptothecin derivatives or pharmaceutically acceptable hydrochloride of the camptothecin derivatives is used for preparing antitumor drugs for treating diseases or symptoms such as colorectal cancer.

Description

technical field [0001] The invention belongs to the field of organic synthesis, and relates to a camptothecin derivative, a preparation method thereof and research on preparation of anti-colorectal cancer drugs. The invention transforms the compound with good inhibitory effect on colorectal cancer with SN38 as the basic skeleton through structure modification. Background technique [0002] Colorectal cancer is one of the common malignant tumors in my country. In recent years, the incidence and mortality of colorectal cancer in my country have maintained an upward trend. The 2018 China Cancer Statistics Report shows that the incidence and mortality of colorectal cancer in my country rank first among all malignant tumors. Ranking 3rd and 5th, including 376,000 new cases and 191,000 deaths, China has become the country with the largest number of new cases and deaths of colorectal cancer in the world every year, and colorectal cancer seriously affects and threatens Chinese reside...

Claims

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Application Information

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IPC IPC(8): A61K31/7072A61P35/00
CPCA61K31/7072A61P35/00
Inventor 田京伟王洪波刘宗亮李敏刘妍杰刘雪村李小鹏
Owner YANTAI UNIV
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