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Preparation and application of tetrahydrofolic acid ring-opened analogs with aziridine structure

A kind of technology of aziridine and tetrahydrofolate, applied in the field of medicine

Inactive Publication Date: 2013-12-18
PEKING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, so far, there has been no literature report on inhibitors targeting methionine synthase. Therefore, using methionine synthase as a new target to develop its inhibitors may overcome the shortcomings of current clinically used anti-tumor drugs.

Method used

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  • Preparation and application of tetrahydrofolic acid ring-opened analogs with aziridine structure
  • Preparation and application of tetrahydrofolic acid ring-opened analogs with aziridine structure
  • Preparation and application of tetrahydrofolic acid ring-opened analogs with aziridine structure

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0013] Compound 1: Ethyl 4-methylaminobenzoate

[0014]

[0015] Ethyl 4-aminobenzoate (1.65g, 10mmol) was dissolved in 15mL of dry acetonitrile, anhydrous K was added 2 CO 3 (0.76g, 5.5mmol), stirred for 15 minutes and added CH 3 I (0.69mL, 11mmol), stirred at room temperature for 48h. Inorganic salts were removed by filtration, and the filtrate was concentrated under reduced pressure and then purified by silica gel column chromatography. The eluent was petroleum ether: ethyl acetate (9:1), and 0.77 g of the title compound was obtained as a white solid. The yield was 62%, m.p.61~ 62°C.

[0016] Compound 2: Diethyl N-(4-methylamino)benzoyl-L-glutamate

[0017]

[0018] According to the preparation method of compound 1, 1.05 g of the title compound was obtained as a white solid, with a yield of 64%, m.p.88-89°C.

[0019] Compound 3: Ethyl 4-(N-methyl-N-allyl)aminobenzoate

[0020]

[0021] Dissolve ethyl 4-methylaminobenzoate (1.79 g, 10 mmol) in anhydrous DMF (1...

Embodiment 2

[0120] Example 2 Evaluation of the biological activity of methionine synthase and dihydrofolate reductase on the synthesized compound

[0121] 1. Determination of inhibitory activity against methionine synthase (MS)

[0122] 1.1 Experimental principle:

[0123] Tetrahydrofolate, one of the products of the enzymatic reaction, can quantitatively react with formic acid solution under strong acidic and heating conditions, and derivatize to generate CH+=H 4 Folate has strong absorption at 350nm. The reaction substrate methyltetrahydrofolate and other compounds in the reaction system do not react with formic acid, and the absorption at 350nm is very small. Therefore, the stronger the inhibitory effect of the test compound on methionine synthase, the less the amount of tetrahydrofolate produced after the enzymatic reaction, and the weaker the absorption at 350nm.

[0124] 1.2 Experimental method:

[0125] Take HL-60 cells in the logarithmic growth phase, and use 1×10 6 The numbe...

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Abstract

Based on the action mechanism of methionine synthase and the structure of folic acid compounds, the invention designs tetrahydrofolic acid ring-opened analogs with an aziridine structure, which are used as methionine synthase inhibitors, and specifically provides a nitrogen heterocyclic three-membered ring structure (general formula I) of which the nucleophilic reactivity is stronger than that of methyltetrahydrofolic acid. The nitrogen heterocyclic three-membered ring structure can form covalent bonds with the methionine synthase (monovalent cobalamin) having super-strong nucleophilicity so as to carry out irreversible binding, thus resulting in the inactivation of the methionine synthase. In the general formula I, the definition of each group is as described in the claims. Biological activity tests show that the tetrahydrofolic acid ring-opened analogs have strong inhibition activity on the methionine synthase and simultaneously present certain inhibition activity on dihydrofolate reductase, so that the tetrahydrofolic acid ring-opened analogs are likely to be a new class of potential multi-target antitumor drugs.

Description

technical field [0001] This application involves designing and synthesizing a class of tetrahydrofolate ring-opening analogs with aziridine structure based on the structure of folic acid compounds and the mechanism of action of methionine synthase, and carried out biological activity tests. The tetrahydrofolate ring-opened analogs with aziridine structure designed and synthesized by the present inventors have stronger reactivity than methyltetrahydrofolate, and have shown higher methionine synthase inhibitory activity through activity tests, and have Certain dihydrofolate reductase inhibition. The invention belongs to the technical field of medicine. Background technique [0002] Cancer is a major disease that endangers human life and health. According to WHO statistics, the number of cancer deaths in the world every year is as high as 7.9 million, and the number of new cases is 8.7 million, and the number is still increasing year by year. It has become second only to cardi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/04C07D239/52C07D239/48C07D239/545A61K31/506A61K31/505A61P35/00
Inventor 邓喜玲刘俊义
Owner PEKING UNIV
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