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Compound N-total trans dimension methanamide derivative and its preparation method and application

A retinoic acid, all-trans technology, applied in the field of chemistry, can solve the problems of retinoic acid not reaching the effective inhibitory concentration, liver function damage, toxic and side effects, etc. Effect

Inactive Publication Date: 2005-04-20
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0002] Retinoic acid has been used in the induction of tumor differentiation for many years, and has made great achievements in the treatment of leukemia and other tumors. The complete remission rate of promyelocytic leukemia induced by single drug reached 89%. Some studies have found that the application of retinoic acid in patients with liver cancer cannot reach Effectively inhibit the concentration, but also produce serious side effects and retinoic acid syndrome, such as liver function damage, drug resistance and relapse after induction of remission, and ineffective for recurrent cases, so retinoic acid is actually effective for the treatment of liver cancer patients. very restrictive

Method used

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  • Compound N-total trans dimension methanamide derivative and its preparation method and application
  • Compound N-total trans dimension methanamide derivative and its preparation method and application
  • Compound N-total trans dimension methanamide derivative and its preparation method and application

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Effect test

Embodiment 1

[0033] Use all-trans retinoic acid dry powder as synthetic raw material, react with benzene and phosphorus trichloride, and stir for 2.5 hours under the protection of nitrogen, an orange-red solution appears, a small amount of phosphorous acid precipitates on the wall of the reaction bottle, and continues to Stir under protection for 15 minutes, transfer to a dry layered funnel, separate the benzene solution that generates retinoyl chloride, stir in an ice bath for 10 minutes, add dropwise ice-cold L-proline, which has been pre-prepared Dissolve in 2m01 / l sodium hydroxide solution, continue to stir, and adjust the pH of the solution with 2m01 / l sodium hydroxide solution, keep it above 9.0, go to the ice bath, stir the reaction solution overnight, and divide the reaction solution into Two layers, the upper layer is brownish-yellow, the lower layer is darker in color, extracted three times with ether, the upper layer is added to a silica gel column for chromatography, samples are...

Embodiment 2

[0035] Functional test of the compound of the present invention

[0036] 1. Effects on the cycle of liver cancer cells:

[0037] Hep3B liver cancer cells were treated with different concentrations, and then the cell cycle was detected by flow cytometry to observe the effect of N-all-trans retinamide proline (ATRP) on the cycle of liver cancer cell Hep3B cells. The results showed that N-all-trans Retinamide proline has an effect at 1 μmol / l, and there is a significant difference in the change of cell cycle when it is 3 μmol / l. The period of action is mainly in the G2-M phase, which increases the ratio of G2-M phase cells. Even liver cancer Most of the cells stay in the G2-M phase. Table 1 is the cell cycle analysis.

[0038] 2. Effect on the expression of Lew" antigen on the surface of liver cancer cells:

[0039] N-all-trans retinamide proline acts on Hep3B liver cancer cells for 1-3 days, and then detects and observes the expression of Lewis antigen on the cell surface with ...

Embodiment 3

[0047] N-all-trans retinamide proline of the present invention was compared with all-trans retinoic acid (ATRA) and -4-aminophenol retinamide (4HPR). All-trans retinoic acid 10μM concentration acts on Hep3B cells for 3 days, 4-aminophenol retinamide and N-all-trans retinoic acid amide proline are both 3 μM on Hep3B cells for 3 days, and the cells are collected for enzyme activity. As a result, after Hep3B liver cancer cells were treated with N-all-trans-retinamide proline for 3 days, the activity of α-1,6FT increased from 150.51±68.94 in the control to 266.47±11.91pmol / hr.mg, the two groups The difference was significant (P=0.0007). However, there is no significant difference in the effects of all-trans retinoic acid and 4-aminophenol retinoic acid, indicating that the compound of the present invention has a strong regulatory effect on liver cancer cell α-1, 6FT activity, and the concentration of action is 3.3 times lower than that of ATRA , while all-trans retinoic acid and ...

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Abstract

The invention belongs to the field of chemistry, and specifically relates to N-all-trans retinamide derivatives, a preparation method thereof and an antitumor application thereof. The present invention adopts molecular simulation structure design, uses all-trans retinoic acid dry powder as raw material to react with benzene and phosphorus trichloride, and is prepared after synthesis and purification by stirring under nitrogen, ether extraction, chromatography, mass spectrometry analysis, etc., and the present invention derives The molecule has the following general structure. The present invention has been proved by experiments that it has an obvious regulating effect on α16 fucose glycosyltransferase, is less toxic than retinoic acid, has a strong inhibitory effect on liver cancer cells, and has the effect of significantly inhibiting the metastasis potential of liver cancer cells in nude mice, and can be prepared A new type of antineoplastic drug with high potential social benefits and application prospects. ∴

Description

technical field [0001] The invention belongs to the field of chemistry, and specifically relates to a compound N-all-trans retinoic acid derivative, a preparation method thereof and an antitumor application thereof. Background technique [0002] Retinoic acid has been used in the induction of tumor differentiation for many years, and has made great achievements in the treatment of leukemia and other tumors. The complete remission rate of promyelocytic leukemia induced by single drug reached 89%. Some studies have found that the application of retinoic acid in patients with liver cancer cannot reach Effectively inhibit the concentration, but also produce serious side effects and retinoic acid syndrome, such as liver function damage, drug resistance and relapse after induction of remission, and ineffective for recurrent cases, so retinoic acid is actually effective for the treatment of liver cancer patients. Very restrictive. It is known in the art that the effects of retinoi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D207/16A61K31/401A61P35/00
Inventor 吴兴中
Owner FUDAN UNIV
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