Introduction |
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Azathioprine, an imidazole derivative of mercaptopurine, is decomposed into mercaptopurine in the body to work. Its immune mechanism is the same as mercaptopurine, that is,
it has a purine antagonistic effect. Since immune active cells need purine substances during the proliferation period after antigen chemicalbook stimulation,
purine antagonism at this time can inhibit the synthesis of DNA, RNA and protein, thereby inhibiting the proliferation of lymphocytes,
that is, preventing antigen-sensitive lymphocytes from transforming into immune blasts and producing immune effects. |
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Pharmacological action |
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Azathioprine is a commonly used immunosuppressant in clinical practice. It is a derivative of 6-MP and has a significant inhibitory effect on both humoral immunity and cellular immunity,
inhibiting the synthesis of DNA and RNA. After oral absorption, this product is converted into 6-mercaptopurine in the body, exerting an anti-purine metabolic effect,
preventing lymphocyte proliferation, and producing an immunosuppressive effect. It is mainly used to inhibit immune rejection during organ transplantation. In dermatology,
it is used to treat lupus erythematosus, pemphigus, pemphigoid, scleroderma, sarcoidosis, psoriasis, Behcet's disease, purpura, allergic vasculitis, Wegener's granulomatosis,
mycosis fungoides, pityriasis rubra pilaris, atopic dermatitis, acne fulminans, etc. In addition, it is also used for rheumatoid arthritis, ulcerative colitis, myasthenia gravis,
chronic nephritis and nephrotic syndrome. |
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Biological Activity |
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Azathioprine is an immune suppressant drug that inhibits the synthesis of purines and the activation of the GTP-binding protein Rac1. It is used in organ transplantation and autoimmune diseases. |
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Target |
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Target | Value |
Rac1 |
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() |
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In vitro studies |
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In primary human CD4+ T lymphocytes, Azathioprine inhibits the activation of Rac1 target genes such as mitogen-activated protein kinase kinase (MEK), NF-κB, and bcl-X(L),
leading to the mitochondrial pathway of apoptosis. Azathioprine converts a co-stimulatory signal into an apoptotic signal by modulating the activity of Rac1. Azathioprine generates 6-thio-GTP,
thereby preventing the development of an effective immune response via Vav activity against Rac proteins. Azathioprine (1mChemicalbookM) restores ATP levels and prevents cell damage,
while culturing in glucose-rich medium enhances ATP levels and ameliorates cell death. Azathioprine reduces viability by 5-34% at 1 day and 42-92% at 4 days. In primary cultured rat hepatocytes,
Azathioprine reduces hepatocyte viability and induces the following events: intracellular reduction of glutathione (GSH) depletion, decreased metabolic activity, and release of lactate dehydrogenase.
In intact isolated rat liver mitochondria, the effects of azathioprine on hepatocytes were associated with dilatation and increased oxygen consumption. |
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In vivo studies |
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In mouse rat brain transplants, the combination of azathioprine and cyclosporin A or prednisolone resulted in 14/15 transplant survival (93%) compared to 11/14 (79%) in the control group. |
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Precautions |
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①Since azathioprine has many and serious adverse reactions, it is not the first choice for autoimmune diseases. It is usually used when the disease cannot be controlled by corticosteroids alone.
②This drug should not be used in patients with hypoxanthine-guanine-phosphoribosyltransferase deficiency (Lesch-Nyhan syndrome).
③This drug should be used with caution in patients who are receiving or have recently completed treatment with cytostatics or bone marrow suppressive drugs (such as penicillamine).
④This drug is contraindicated in patients with rheumatoid arthritis who have been treated with alkylating agents (including cyclophosphamide, chlorambucil, and melphalan) because it may increase the risk of malignant tumors.
⑤After organ transplantation, long-term treatment should be maintained, otherwise the expected rejection reaction will occur.
⑥As with all cytotoxic chemotherapy drugs, spouses of patients treated with this drug need to take adequate contraceptive measures.
⑦Patients at increased risk of skin cancer should minimize exposure to sunlight and ultraviolet light by wearing protective clothing and using sunscreen products with high protection factors.
⑧People who are allergic to mercaptopurine may also be allergic to this drug. |
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Chemical properties |
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This product is a light yellow powder or crystalline powder; odorless; slightly bitter. Very slightly soluble in ethanol, almost insoluble in water; easily soluble in dilute ammonia solution. |
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Uses |
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Azathioprine is one of the derivatives of the chemical synthesis 6-mercaptopurine and is an immunosuppressant. It is a derivative of mercaptopurine,
which decomposes into mercaptopurine in the body to work. It is mainly used to inhibit immune rejection during allogeneic transplantation,
and is often used in combination with corticosteroids. It is also widely used in autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, autoimmune hemolytic anemia,
thrombocytopenic purpura, active chronic hepatitis, ulcerative colitis, myasthenia gravis, scleroderma, etc. Blood counts should be strictly checked during medication;
it is contraindicated in patients with impaired liver function. When used in combination with corticosteroids, the oral cavity is susceptible to viral infections such as herpes zoster,
herpes simplex and varicella. It is contraindicated for pregnant women. |
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Uses |
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Used as an immunosuppressant and anti-tumor drug. |
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Production method |
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Use diethyl oxalate as raw material, and obtain it through amination, cyclization, chlorination, nitration and condensation.
1. Amination: Add diethyl oxalate and methanol into a reaction pot, cool to below 20℃, pass dry methylamine gas to saturation, and then cool to below 10℃, precipitate crystals, filter and dry to obtain oxalyl dimethylamine, with a melting point of 210-212℃ and a yield of 95.8%.
2. Cyclization and chlorination: Add excess oxalyl dimethylamine and phosphorus pentachloride into the reaction pot in batches, keep warm at 70-80℃ for 2h, leave overnight, evaporate phosphorus oxychloride under reduced pressure, the temperature does not exceed 100℃, cool, add ice water, stir, adjust the pH to 9-10 with 30-40% alkali solution, and let it stand. Separate the oily substance, cool the mother liquor, filter after the inorganic salt is precipitated, wash with chloroform, and extract the mother liquor with chloroform. Combine the oil layer and the chloroform layer, recover the chloroform, distill under reduced pressure, collect the fraction with a boiling point of 110-115℃ (4.0kPa), and obtain 1-methyl-5-chloroimidazole. The yield is 52%.
3. Nitration Add 1-methyl-5-chloroimidazole to a glass-lined reaction pot, and then add nitric acid under cooling. Continue to add sulfuric acid dropwise under cooling, and after addition, react at 100℃ for 2h, cool again, add ice water to precipitate the product, and filter and dry to obtain 5-chloro-1-methyl-4-nitroimidazole. The yield is 86%.
4. Condensation Boil 6-mercaptopurine, sodium hydroxide, water and 5-chloro-1-methyl-4-nitroimidazole together for 4h, and adjust the pH of the reaction product with acetic acid until thiothiopurine is precipitated. |
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Category |
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Toxic substances |
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Toxicity classification |
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Poisoning |
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Acute toxicity |
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Oral-rat LD50: 535 mg/kg; Oral-mouse LD50: 1389 mg/kg |
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Flammability Hazard Characteristics |
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Can burn to produce toxic nitrogen and sulfur oxide fumes; Side effects after use by patients: changes in liver function,
hypermotility of the gastrointestinal tract, nausea, vomiting, diarrhea, fever, low blood pressure, low urine volume, no urine |
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Storage and transportation characteristics |
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Ventilation, low temperature and drying |
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Fire extinguishing agents |
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Dry powder, foam, sand, carbon dioxide, mist water |
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