ChemicalBook > Product Catalog > API > Synthetic Anti-infective Drugs > Antiviral drugs > Zidovudine
Zidovudine Chemical Properties
- Melting point:113-115 °C(lit.)
- alpha D25 +99° (c = 0.5 in water)
- Boiling point:410.43°C (rough estimate)
- Density 1.3382 (rough estimate)
- refractive index 47 ° (C=1, H2O)
- Flash point:9℃
- storage temp. −20°C
- solubility H2O: 50 mg/mL
- pkapKa 9.53(H2O t = 25.0±0.1 I = 0.00) (Uncertain)
- form Powder
- color White to Off-white
- Water Solubility 1-5 g/100 mL at 17 ºC
- Sensitive Light Sensitive & Hygroscopic
- Merck 14,10123
- BRN 3595791
- CAS DataBase Reference30516-87-1(CAS DataBase Reference)
- IARC2B (Vol. 76) 2000
- EPA Substance Registry SystemThymidine, 3'-azido-3'-deoxy- (30516-87-1)
- Hazard Codes Xn
- Risk Statements 40-36/37/38-20/21/22
- Safety Statements 36/37/39-45-36-26
- RIDADR UN1230 - class 3 - PG 2 - Methanol, solution
- WGK Germany 3
- RTECS XP2072000
- F 10
- Hazard Note Harmful
- HS Code 29349990
- Hazardous Substances Data30516-87-1(Hazardous Substances Data)
- ToxicityLD50 in male, female mice, male, female rats (mg/kg): 3568, 3062, 3084, 3683 orally; >750 i.v. (all species) (Ayers)
Zidovudine Usage And Synthesis
- DescriptionZidovudine, also known as azidothymidine (AZT), is an antiviral agent acting via reverse transcnptase inhibition. It was first launched in the U.K. and subsequently introduced in over a dozen countries for the management of severe manifestations of HIV infection. In patients with AIDS and ARC, zidovudine reduces the risk of opportunistic infections and prolongs survival time. In symptom-free patients it shows promise in halting further immunological deterioration.
- Chemical PropertiesOff White Crystalline Powder
- OriginatorDetroit Inst. Cancer Res. (USA)
- UsesA potent and selective inhibitor of HIV-1 replication
- UsesZidovudine is an antiretroviral drug that is clinically active against HIV-1 and is intended
to treat HIV-infected patients. Zidovudine is an analog of thymidine that inhibits replication of the AIDS virus. It also turned into mono-, di-, and triphosphates by the same cellular enzymes that catalyze phosphorylation of thymidine and thymidine nucleosides.
Zidovudine-triphosphate is then included in the terminal fragment of the growing chain of
viral DNA by viral reverse transcriptase, thus causing the viral DNA chain to break apart
in cells infected with the virus.
Zidovudine has been authorized for treating patients with AIDS. It significantly prolongs the life of the patient, although it has a number of toxic effects. Synonyms of this drug are azidothymidine and retrovir.
- DefinitionChEBI: A pyrimidine 2',3'-dideoxyribonucleoside compound having a 3'-azido substituent and thymine as the nucleobase.
- IndicationsZidovudine was the first agent to be used to prevent the transmission of HIV from a pregnant woman to her child. It was given to the mother at 14 to 34 weeks’ gestation and to the child for the first 6 weeks of life. Current combination therapies employ zidovudine with another NRTI and a protease inhibitor.
- Manufacturing ProcessPreparation of 2,3'-anhydrothymidine
Thymidine (85.4 g; 0.353 mol) was dissolved in 500 mL dry DMF (dimethyl formamide) and added to N-(2-chloro-1,1,2-trifluoroethyl)diethylamine (100.3 g; 0.529 mol) [prepared according to the method of D. E. Ayer, J. Med. Chem. 6, 608 (1963)]. This solution was heated at 70°C for 30 minutes then poured into 950 mL ethanol with vigorous stirring. The product precipitated from this solution and was filtered. The ethanol supernatant was refrigerated then filtered to yield a total of 47.75 g (0.213 mol; 60.3%) of 2,3'- anhydrothymidine; melting point 228°-230°C.
Preparation for 3'-azido-3'-deoxythymidine
2,3'-Anhydrothymidine (25 g; 0.1115 mol) and NaN 3 (29 g; 0.446 mol) was suspended in a mixture of 250 mL DMF and 38 mL H 2 O. The reaction was refluxed for 5 hours at which time it was poured into 1 liter of H 2 O. This aqueous solution was extracted with ethyl acetate (EtOAc) (3x700 ml). The EtOAc was dried over Na 2 SO 4 , filtered, and then EtOAc was removed in vacuo to yield a viscous oil. This oil was stirred with 200 mL water resulting in a solid, 3'-azido-3'-deoxythymidine, 9.15 g (0.0342 mol); 30.7%; melting point 116°-118°C.
- brand nameRetrovir (GlaxoSmithKline).
- Therapeutic FunctionAntiviral, Antineoplastic
- Antimicrobial activityZidovudine is active against HIV-1, HIV-2 and HTLV-1.
- Acquired resistanceAs with stavudine, mutations at position 41, 67 and 70, and positions 210, 215 and 219 (the ‘thymidine analog mutations’) of the reverse transcriptase genes are associated with diminished antiretroviral efficacy.
- General DescriptionSlightly off-white odorless powdery solid.
- General DescriptionZidovudine, 3'-azido-3'-deoxythymidine or AZT, is ananalog of thymidine that possesses antiviral activityagainst HIV-1, HIV-2, HTLV-1, and several other retroviruses.This nucleoside was synthesized in 1978 by Linand Prusoff as an intermediate in the preparation ofamino acid analogs of thymidine. A screening program directedtoward the identification of agents potentially effectivefor the treatment of patients with AIDS led to the discoveryof its unique antiviral properties 7 years later.
Zidovudine is recommended for the management of adultpatients with symptomatic HIV infection (AIDS or ARC)who have a history of confirmed Pneumocystis carinii pneumoniaor an absolute CD4+(T4 or TH cell) lymphocytecount below 200/mm3 before therapy. The hematologicaltoxicity of the drug precludes its use in asymptomatic patients.Anemia and granulocytopenia are the most commontoxic effects associated with AZT.
- Air & Water ReactionsDust may form an explosive mixture in air. Water soluble. Hydrolysis occurs in strongly basic solutions .
- Reactivity ProfileZidovudine is a azido compound. Azo, diazo, azido compounds can detonate. This applies in particular to organic azides that have been sensitized by the addition of metal salts or strong acids. Toxic gases are formed by mixing materials of this class with acids, aldehydes, amides, carbamates, cyanides, inorganic fluorides, halogenated organics, isocyanates, ketones, metals, nitrides, peroxides, phenols, epoxides, acyl halides, and strong oxidizing or reducing agents. Flammable gases are formed by mixing materials in this group with alkali metals. Explosive combination can occur with strong oxidizing agents, metal salts, peroxides, and sulfides.
- Fire HazardFlash point data for Zidovudine are not available; however, Zidovudine is probably combustible.
- Pharmaceutical ApplicationsAn analog of thymidine formulated for oral or intravenous use.
- Mechanism of actionZidovudine (AZT , ZDV) is an analogue of thymidine in which the azido group is substituted at the 3-carbon atom of the dideoxyribose moiety. It is active against RNA tumor viruses (retroviruses) that are the causative agents of AIDS and T-cell leukemia. Retroviruses, by virtue of RT, direct the synthesis of a provirus (DNA copy of a viral RNA genome). Proviral DNA integrates into the normal cell DNA, leading to the HIV infection. Zidovudine is converted to 5′-mono-, di-, and triphosphates by the cellular thymidine kinase. These phosphates are then incorporated into proviral DNA, because RT uses ZDV-triphosphate as a substrate. This process prevents normal 5′,3′-phosphodiester bonding, resulting in termination of DNA chain elongation because of the presence of an azido group in ZDV. The multiplication of HIV is halted by selective inhibition of RT and, thus, viral DNA polymerase by ZDV-triphosphate at the required dose concentration. Zidovudine is a potent inhibitor of HIV-1, but it also inhibits HIV-2 and EBV.
- PharmacokineticsOral absorption: 65%
Cmax 300 mg twice daily: 2.3 mg/L
Plasma half-life: 1.1 h
Volume of distribution: 1.6 L/kg
Plasma protein binding; 34–38%
Absorption and distribution
It is absorbed rapidly and almost completely following oral administration. Absorption is not significantly affected by food. It appears to undergo widespread body distribution. CNS penetration is fairly good. The semen:plasma ratio varies from 0.95 to 13.5 (mean 5.9). It is secreted into breast milk.
Metabolism and excretion
Following hepatic metabolism (glucuronidation), elimination is primarily renal. After oral administration, urinary recovery of zidovudine and its glucuronide metabolite accounted for 14% and 74% respectively of the dose, with a total urinary recovery of 90%.
In severe renal impairment, clearance was about half that reported in subjects with normal renal function Accumulation may occur in patients with hepatic impairment due to decreased glucuronidation.
- Clinical UseTreatment of HIV infection in adults and children (in combination with
other antiretroviral drugs)
Reduction of maternal transmission of HIV to the fetus
- Side effectsIn common with other drugs in this class, use has been associated
with episodes of fatal and non-fatal lactic acidosis
and hepatomegaly with steatosis. Careful clinical evaluation
is needed in patients with evidence of hepatic abnormality.
Myelosuppression may occur within the first 4–6 weeks of
therapy. Hematological parameters should be monitored during
this period, with prompt dose modification or switch if
abnormalities are observed. Treatment with reduced doses
may be attempted in some patients once bone marrow recovery
has been observed. Myopathy is rarely seen with the use
of the current dosing regimens.
Co-administration with drugs known to cause nephrotoxicity, cytotoxicity or which interfere with red or white blood cell number and function may increase the risk of toxicity. Probenecid and trimethoprim may reduce renal clearance of zidovudine, and other drugs that are metabolized by glucuronidation may interfere with its metabolism.
- Safety ProfileModerately toxic by intravenousroute. Human systemic effects by ingestion: aplasticanemia, changes in blood cell count, convulsions or effect on seizure threshold, headache, nails, retinal changes.Human mutation data reported.
- Chemical SynthesisZidovudine is 3-azido-3-deoxytimidine (36.1.26), is synthesized from
1-(2-deoxy-5-O-trityl-β-D-lyxosyl)thymine, which is treated with methansulfonyl chloride in pyridine to make the corresponding mesylate 36.1.24. Replacing the methyl group
with an azide group using lithium azide in dimethylformamaide makes the product 36.1.25
with inverted configuration at C3 of the furanosyl ring. Heating this in 80% acetic acid
removes the trityl protection, giving zidovudine.
- Veterinary Drugs and TreatmentsIn veterinary medicine, zidovudine may be useful for treating feline immunodeficiency virus (FIV) or feline leukemia virus (FeLV). While zidovudine can reduce the viral load in infected cats and improve clinical signs, it may not alter the natural course of the disease to a great extent.
Zidovudine Preparation Products And Raw materials
- Stavudine Lamivudine scriptene 3'-AZIDO 3'-DEOXYTHYMIDINE 5'-DI-PHOSPHATE, TRITRIETHYLAMMONIUM SALT 3'-azido-3'-deoxythymidine 5'-diphosphate 5'-O-BENZOYL-3'-AZIDO-3'-DEOXYTHYMIDINE Thiophanate-methyl Bensulfuron methyl Sodium azide Deoxidizer DNA, SINGLE STRANDED, IMM. ON CELLULOSE, FROM CALF THYMUS* Methyl ETHYL AZIDOACETATE Methyl acrylate Methylparaben Diphenylphosphoryl azide Parathion-methyl Zidovudine
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