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Vulcanized aspartic acid modified melatonin derivative and application thereof

A compound, halogen technology, applied in the field of tumor drugs, can solve the problems of inconvenient administration, no curative effect, high cost, etc.

Active Publication Date: 2012-12-12
冉瑞琼
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Traditional antioxidants, such as glutathione (GSH), Vit-E, Vit-C, CoA-Q10, glutamine, methionine, superoxide dismutase (SOD), etc. have not been obtained clinically Definite efficacy, which may be due to insufficient strength of protection and lack of selectivity
Drugs that have been used to alleviate the side effects of radiotherapy, such as amifostine (amifostine), dexrazoxane (Dexrazoxane), these protective agents all have the following limitations: 1) have strong side effects themselves: the therapeutic dose of amifostine and The poisoning dose is very close, and it is easy to cause hypotension, dizziness or fainting after taking the medicine. The incidence of these side effects is as high as 80%. Dexrazoxane itself causes leukopenia (the incidence of leukopenia is as high as 78%)
3) Inconvenient administration, intravenous administration is only effective, and the cost is high
However, until today, it has still not been successfully used clinically. The reasons are: 1) interfere with the therapeutic effect of radiotherapy and chemotherapy on tumors, and cannot selectively protect only normal tissues; 2) the strength of protection is not enough to reduce high doses. oxidative damage caused by radiation and large doses of chemotherapeutics; 3) the body is prone to tolerance to melatonin compounds, and the protective effect lasts less than a complete cycle of radiotherapy and chemotherapy; 4) it has certain side effects, and high doses Melatonin is mainly manifested as sleep disorders and mental depression; 5) the protective surface is not wide enough, and it does not have a protective effect on certain specific radiotherapy and chemotherapy injuries
No one has yet developed such drugs with satisfactory efficacy

Method used

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  • Vulcanized aspartic acid modified melatonin derivative and application thereof
  • Vulcanized aspartic acid modified melatonin derivative and application thereof
  • Vulcanized aspartic acid modified melatonin derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Embodiment 1: In this embodiment, compounds represented by formulas 2-5 and metal salts thereof were synthesized respectively.

[0059] a. the synthesis of the melatonin magnesium salt / zinc salt modified by aspartic acid sulfide of formula 2

[0060] In this example, the compound of formula 2 was synthesized according to the scheme shown below:

[0061]

[0062]

[0063] Step 1. Synthesis of sulfurized aspartic acid: (1) 60% NaH (1.8mmol) is suspended in THF (5ml) at 0-4°C, and 1 equivalent of methylphosphorous acid (CH 3 -SO 2 -H 2 PO 3 ), 1 equivalent of aspartaldehyde (commercial product, purchased from Sigma- Eldrich Company, compound 1a) was added therein, stirred at room temperature for 30 minutes, then added 1 equivalent of acetaldehyde (aldehyde), and continued to stir at room temperature for 120 minutes to generate aspartic acid sulfide (compound 1b) with a protective agent; (2) add 1 equivalent of trifluoroacetic acid (TAF) to react at 0-4°C for 60 ...

Embodiment 2

[0075] Example 2: Experiment of the protective effect of the compound synthesized in Example 1a and its zinc salt as a protective agent against human peripheral leukocyte damage caused by cobalt-60γ-rays.

[0076] In this example, isolated healthy human peripheral leukocytes (lymphocytes) were cultured in 96-well cell culture plates in RPMI1640 medium (containing 10% newborn calf serum, 1000 IU / ml recombinant human interleukin-2, 1% penicillin , 1% streptomycin) in conventional culture. Melatonin (raw material 2a used to prepare the compound of formula 2 in Example 1a), and aspartic acid melatonin sulfide (compound 2b) and aspartic acid melatonin zinc sulfide prepared in Example 1a (compound 3b), amifostine (a protective agent that has been used clinically as a positive control) was added as a protective agent to human peripheral leukocytes cultured in vitro, and the final concentrations were: melatonin (3μM and 15μM) and asparagus sulfide melatonin (3 μM and 15 μM), zinc asp...

Embodiment 12

[0098] Example 12 Indomethacin combined with the protective agent of the present invention has the tumor inhibitory effect and normal tissue selective effect on γ-ray-induced transplanted tumors in nude mice (in vivo experiment)

[0099] In this example, the product synthesized in Example 1a (ie, the zinc salt of the compound of formula 2) was used for experiments. Under sterile conditions, the breast cancer cell (MCF-7) suspension in the logarithmic growth phase (adjust the cell concentration to 1×10 with normal saline) 7 w / mL) was inoculated subcutaneously on the right axillary back of experimental female nude mice. 6 / only. After 10 days, a 4-6 mm subcutaneous transplanted tumor appeared. The tumor-bearing nude mice were randomly divided into groups with 3 mice in each group. (1) Control group, without any treatment; (2) Irradiation group, without any protective agent; (3) Radiation therapy + melatonin zinc aspartate sulfide; (4) Radiation therapy + indomethacin; (5) Ra...

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Abstract

The invention relates to a tumor drug, and provides a vulcanized aspartic acid modified melatonin derivative shown in the following formula and application thereof, wherein a group R1 is selected from H, C1-C4 alkyl or C2-C4 alkenyl; a group R2 is selected from hydrogen or halogen; and a group R3 is selected from C1-C4 alkyl or C2-C4 alkenyl or a group shown in the description. The derivative can be applied by cancer patients receiving chemotherapy and radiation therapy, and toxic and side effects of chemoradiotherapy of malignant tumors can be reduced. The invention also provides a drug containing the derivative and indomethacin, and the drug has a function of selectively protecting normal cells.

Description

technical field [0001] The invention relates to the field of tumor drugs, more specifically, the invention provides a compound that can reduce the side effects of malignant tumor radiotherapy and chemotherapy. Background technique [0002] Chemotherapy and radiotherapy are the main treatment methods for cancer patients, but these two treatments face common challenges in clinical practice. A big problem that people face is the toxic and side effects of these treatments. This is due to the lack of targeted selectivity of these two treatments for normal tissue cells and cancer cells, but the same lethality occurs, even for proliferation. The damage of fast bone marrow cells, endothelial cells, epithelial cells, and gastrointestinal mucosal cells is more obvious. Therefore, while killing cancer cells, normal cells often suffer extensively. Patients receiving treatment often experience adverse reactions such as oral ulcers, loss of appetite, diarrhea, hair loss, and decreased w...

Claims

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Application Information

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IPC IPC(8): C07D209/14C07D401/12A61K31/454A61K31/405A61K31/4045A61P39/02
Inventor 冉瑞琼
Owner 冉瑞琼
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