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A kind of camptothecin glycoconjugate and its preparation method and application

A technology of glycoconjugates and camptothecin, applied in the field of camptothecin glycoconjugates and its preparation, can solve the problem of high cytotoxicity and achieve the effect of inhibiting DNA topoisomerase

Active Publication Date: 2021-01-26
GUANGDONG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, camptothecin is highly cytotoxic to normal cells

Method used

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  • A kind of camptothecin glycoconjugate and its preparation method and application
  • A kind of camptothecin glycoconjugate and its preparation method and application
  • A kind of camptothecin glycoconjugate and its preparation method and application

Examples

Experimental program
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Effect test

Embodiment 1

[0068] This embodiment carries out the preparation of camptothecin glycoconjugate (compound a), comprises the following steps:

[0069] 1) Dissolve D-glucose (2g, 11.1mmol) into a mixed solution of triethylamine (8.5ml, 61.05mmol) and DMF (25ml, 61.05mmol), then cool the solution system to 0 with a low temperature constant temperature reaction bath ℃. Slowly added trimethylchlorosilane (7.75ml, 61.05mmol) dropwise to the solution system at 0°C, and then stirred at room temperature for 4h to carry out the first reaction. The progress of the reaction was detected by TLC. After the reaction was completed, hexane and crushed ice were added to the reaction mixture in sequence. The aqueous solution was extracted with hexane, and the organic phases were combined, washed with water and brine twice in turn, anhydrous Na 2 SO 4 It was dried, concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain 1.632 g of transpar...

Embodiment 2

[0075] This embodiment carries out the preparation of camptothecin glycoconjugate (compound b), comprising the following steps:

[0076] 1) Using D-galactose as the raw material, 9.26 g of transparent oily compound 2 was prepared in the same manner as step 1) of Example 1, with a yield of 62.8%. The NMR data of compound 2 are: 1 H NMR (400MHz, CDCl3) δ = 4.91 (d, J = 2.0, 1H), 3.76 (s, 2H), 3.68 (d, J = 1.8, 2H), 3.52–3.45 (m, 1H), 3.39 (dd , J=9.6, 5.6, 1H), 0.03–-0.05 (m, 45H).

[0077] 2) Using compound 2 as a raw material, 1.663 g of transparent oily compound 6 was prepared in the same manner as step 2) of Example 1, with a yield of 74.67%. The NMR data of compound 6 are: 1 H NMR (400MHz, CDCl3) δ=4.96(d,J=1.7,1H),3.84–3.79(m,1H),3.72–3.67(m,3H),3.67–3.61(m,1H),1.70(d ,J=147.6,1H),0.02–-0.05(m,36H).

[0078] 3) Using compound 6 and compound 9 obtained in Example 1 as raw materials, 50 mg of a light yellow solid, namely compound 11, was prepared in the same manner as i...

Embodiment 3

[0081] This embodiment carries out the preparation of camptothecin glycoconjugate (compound c), comprising the following steps:

[0082] 1) Using D-mannose as a raw material, 9.7 g of transparent oily compound 3 was prepared in the same manner as in step 1) of Example 1, with a yield of 65.8%. The NMR data of compound 3 are: 1 H NMR (400MHz, CDCl3) δ = 4.75 (d, J = 2.0, 1H), 3.70–3.65 (m, 2H), 3.60–3.55 (m, 2H), 3.49 (s, 1H), 3.43 (tdd, J =8.7,5.7,2.5,1H),0.01–-0.03(m,45H).

[0083] 2) Using compound 2 as a raw material, 4.756 g of transparent oily compound 7 was prepared as in step 2) of Example 1, with a yield of 70.45%. The NMR data of compound 7 are: 1 H NMR (400MHz, CDCl3) δ = 4.76 (d, J = 2.1, 1H), 3.72 (t, J = 5.4, 2H), 3.55–3.47 (m, 3H), 1.79 (s, 1H), 0.04–- 0.04(m,36H).

[0084] 3) Using compound 7 and compound 9 obtained in Example 1 as raw materials, 48 ​​mg of a light yellow solid, namely compound 12, was prepared in the same manner as in step 4) of Example 1)...

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Abstract

The invention belongs to the technical field of medicines, and in particular relates to a camptothecin glycoconjugate and its preparation method and application. The invention provides a camptothecin glycoconjugate, and the camptothecin glycoconjugate is synthesized by linking camptothecin and hexose with adipic acid as a linker. Experimental results show that the camptothecin glycoconjugate has an anti-tumor effect, and has high efficiency and low toxicity compared with camptothecin. GLUT1 is widely distributed on the blood-brain barrier and red blood cells. The experimental results show that the camptothecin glycoconjugates of the present invention can be recognized and transported by GLUT1, and enter into tumor cells through the GLUT1 pathway to achieve anti-tumor effects. Moreover, the camptothecin glycoconjugates of the present invention Glycoconjugates, as a cytotoxic quinoline alkaloid, can inhibit DNA topoisomerase (TOPO I).

Description

technical field [0001] The invention belongs to the technical field of medicines, and in particular relates to a camptothecin glycoconjugate and its preparation method and application. Background technique [0002] Malignant tumors, or cancer, are the second leading cause of death in the world. In 2018 alone, there were more than 1.7 million new cancer cases. By 2030, the number of new cancer cases is expected to increase to 23.6 million each year. [0003] Camptothecin is an alkaloid isolated from the fruit of camptothecin. Camptothecin has strong cytotoxic activity and can be used to treat a variety of malignant tumors such as colon cancer, ovarian cancer, bone cancer, bladder cancer and leukemia. Has great grooming value. However, camptothecin is highly cytotoxic to normal cells. Contents of the invention [0004] In view of this, the present invention provides a camptothecin glycoconjugate and its preparation method and application, which are used to solve the probl...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H13/04C07H1/00A61K47/54A61K31/4745A61P35/00
CPCA61K31/4745A61K47/549A61P35/00C07H1/00C07H13/04
Inventor 周渭刘起发臧小豪胡蒙蒙李尤胡锦荣
Owner GUANGDONG UNIV OF TECH
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