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Camptothecin-glycine-norcantharidin conjugate and application thereof

A technology of norcantharidin and glycine is applied in the directions of drug combination, bulk chemical production, organic chemistry, etc., to achieve the effects of high activity, good anti-tumor effect and low cost

Inactive Publication Date: 2019-12-17
ZUNYI MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In general, there may be several cancer genes or pathological pathways for a certain cancer; drug metabolism is still the cause of most tumor treatment failures, and drug resistance is also a frequent problem

Method used

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  • Camptothecin-glycine-norcantharidin conjugate and application thereof
  • Camptothecin-glycine-norcantharidin conjugate and application thereof
  • Camptothecin-glycine-norcantharidin conjugate and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Embodiment 1, preparation compound II

[0021] Referring to the literature, the reaction of furan and maleic anhydride in tetrahydrofuran gives 5,6-didehydronorcantharidin 4, 2), and compound 4 gets norcantharidin by catalytic hydrogenation (such as Pd / C) in tetrahydrofuran 5, 3), compound 5 is subjected to acid anhydride hydrolysis and ring-opening reaction in alcohol reagent ROH to obtain norcantharidic acid monoester II.

[0022]

[0023] R is selected from C 1 -C 6 Alkyl, benzyl, substituted benzyl

[0024] (1), preparation of 5,6-didehydronorcantharidin 4

[0025] Place 12.021 g of maleic anhydride in a dry grinder and grind finely, dissolve in 90 mL of ether, and slowly add 13 mL of furan dropwise. After the reaction solution was reacted at 38°C for 1 h, a white solid appeared in the solution, and the white solid increased with the reaction time. After reacting for 24 hours, suction filtration was performed to obtain the target compound 4 (17.459 g, 85....

Embodiment 2

[0032] Embodiment 2, preparation camptothecin-glycine-norcantharidin conjugate I

[0033] Camptothecin-glycine-norcantharidin conjugate I can be prepared by the following steps: 1), camptothecin and N-Boc-glycine 1 are obtained by esterification reaction in the presence of a coupling agent and an organic base to obtain compound 2; 2), compound 2 is removed Boc protecting group under the catalysis of trifluoroacetic acid to obtain compound 3; 3), and norcantharidin monoester II is obtained camptothecin by esterification in the presence of a coupling agent and an organic base - Glycine-norcantharidin conjugate I.

[0034] Preparation of Compound 2 (BOC-Gly-CPT)

[0035] CPT (160 mg, 0.46 mmol), N-Boc-glycine (1, 160 mg, 0.92 mmol, 2 equ.) and DMAP (0.053 g, 0.45 mmol, 1.0 equ.) were dissolved in CH 2 Cl 2 (20mL). The reaction mixture was cooled to 0 °C. DIC (0.52 mL, 3.35 mmol, 1.3 equ.) was added dropwise to the reaction mixture. The reaction was kept in an ice bath a...

Embodiment 3

[0044] Embodiment 3. Solubility experiment

[0045] Select the synthesized compound Ia and the parent compound camptothecin CPT, dissolve in chloroform at 25°C, and the solubility results are listed in Table 1.

[0046] Table 1. The solubility of compound Ia and CPT in chloroform at 25°C

[0047]

[0048] Compound Ia is many times more soluble in chloroform than CPT. It can be seen that the solubility of synthetic product I in organic solvents is much better than that of CPT.

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Abstract

The invention provides a camptothecin-glycine-norcantharidin conjugate I and a preparation method thereof. R in the formula I is selected from C1-C6 alkyl groups, substituted alkyl groups, cycloalkylgroups, benzyl groups or substituted benzyl groups. Activity tests prove that the designed and synthesized camptothecin-glycine-norcantharidin conjugate I has an excellent antitumor effect, and especially has high activity on liver cancer, stomach cancer, colon cancer and pancreatic cancer. Additionally, the preparation method of the camptothecin-glycine-norcantharidin conjugate I has the advantages of easily available raw materials, low cost, high yield of the target product, and easiness in preparation.

Description

technical field [0001] The invention belongs to the field of new drug design and synthesis, and specifically relates to a novel camptothecin-glycine-norcantharidin conjugate and its antitumor application. Background technique [0002] 20-(S)-Camptothecin (20-(S)-Camptothecin, referred to as CPT) was originally extracted from the bark of Camptotheca acumulate, a Chinese plant of the family Camptotheca, by the team of American medicinal chemist Wani in the early 1960s. It is found in the plant that camptophylla is a kind of broad-leaved tree, which was used in traditional Chinese medicine earlier in our country. Researchers such as Vishnuvajjala and Garzon-Aburbeh have successively reported that camptothecin cannot be used as an anticancer agent in vivo due to high toxicity and low bioavailability. Medicinal chemists have made many attempts to obtain camptothecin derivatives with higher biological activity and enhanced stability. Most of these derivatives involve the modific...

Claims

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Application Information

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IPC IPC(8): C07D519/00A61P35/00
CPCA61P35/00C07D519/00Y02P20/55
Inventor 王先恒赵长阔黄梅袁智
Owner ZUNYI MEDICAL UNIVERSITY
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