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Camptothecin glycoconjugate and preparation method and application thereof

A technology of glycoconjugates and camptothecin sugar, which is applied in the preparation of sugar derivatives, sugar derivatives, sugar derivatives, etc., can solve the problem of high cytotoxicity and achieve the effect of inhibiting DNA topoisomerase

Active Publication Date: 2019-11-08
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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  • Camptothecin glycoconjugate and preparation method and application thereof
  • Camptothecin glycoconjugate and preparation method and application thereof
  • Camptothecin glycoconjugate and preparation method and application thereof

Examples

Experimental program
Comparison scheme
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 medicine, and particularly relates to camptothecin glycoconjugate and a preparation method and application thereof. According to the camptothecin glycoconjugate, the camptothecin glycoconjugate is synthesized and obtained by connecting camptothecin and hexose with adipic acid as spacer. The experimental results show that the camptothecin glycoconjugate has anti-tumor effect, and has the effect of high efficiency and low toxicity compared with the camptothecin. GLUT1 is widely distributed on a blood-brain barrier and red blood cells. The experimental results show that the camptothecin glycoconjugate can be recognized and transported by the GLUT1, and the anti-tumor effect can be achieved by entering tumor cells through a GLUT1 pathway. As a kind of cytotoxicity quinoline alkaloid, the camptothecin glycoconjugate 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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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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