Vidarabine
- Iupac Name：(2R,3S,4S,5R)-2-(6-aminopurin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol
- CAS No.: 5536-17-4
- Molecular Weight：267.24132
- Modify Date.: 2022-11-03 05:31
- Introduction: Vidarabine (adenine arabinoside) is the stereoisomer of adenosine. This analog of a purinenucleoside exhibits selective activity against the herpes virus. The ribose residue is replacedwith an arabinose residue. Like acyclovir, it turns into mono-, di-, and triphosphate in cellsinfected by a virus, thus inhibiting DNA polymerase, and correspondingly preventing DNAsynthesis of the virus approximately 20–40 times more than in “host” cells. It is easily metabolized to a less active, yet nonetheless antiviral compound—arabinosylhypoxanthine. It hasbeen successfully used for herpetic encephalitis, and for complicated shingles. It is used inthe form of eye drops for herpetic keratoconjuctivitis. A synonym of this drug is Vira-A.
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1. Names and Identifiers
- 1.1 Name
- Vidarabine
- 1.2 Synonyms
2'-ARAADENOSINE 6-Amino-9-b-D-arabinofuranosylpurine 6-AMINO-9-BETA-D-ARABINOFURANOSYLPURINE 6-Amino-9-Β-D-arabinofuranosylpurine 9-(b-D-Arabinofuranosyl)adenine 9-(Β-D-arabinofuranosyl)-9H-adenine 9-(Β-D-Arabinofuranosyl)-9H-purin-6-amine 9-(Β-D-glycero-Pentofuranosyl)-9H-purin-6-amine 9-BETA-D-ARABINOFURANOSYLADENINE 9-BETA-D-ARABINOSYLADENINE 9H-Purin-6-amine, 9.Β.-D-arabinofuranosyl- 9H-Purin-6-amine, 9-Β-D-arabinofuranosyl- 9H-purin-6-amine, 9-Β-D-glycero-pentofuranosyl- 9-Β-Arabinoadenosine 9-Β-D-arabinofuranosyl-9H-purin-6-amine 9-Β-D-Arabinofuranosyladenine adenine arabinoside Adenine, 9-Β-D-arabinofuranosyl- Adenine, 9Β-D-arabinofuranosyl- ADENINE-9-BETA-D-ARABINOFURANOSIDE ADENINE-9-BETA-D-ARABINOFURANOSIDE (VIDARABINE) ADENINE-BETA-D-ARABINOFURANOSIDE Adenine-Β-D-arabinofuranoside araA ara-A ara-adenosine ARABINOSYL-ADENINE EINECS 226-893-9 MFCD00065471 Vidarabine Monohydrate
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- 1.3 CAS No.
- 5536-17-4
- 1.4 CID
- 21704
- 1.5 EINECS(EC#)
- 226-893-9
- 1.6 Molecular Formula
- C10H13N5O4 (isomer)
- 1.7 Inchi
- InChI=1S/C10H13N5O4/c11-8-5-9(13-2-12-8)15(3-14-5)10-7(18)6(17)4(1-16)19-10/h2-4,6-7,10,16-18H,1H2,(H2,11,12,13)/t4-,6-,7+,10-/m1/s1
- 1.8 InChIkey
- OIRDTQYFTABQOQ-UHTZMRCNSA-N
- 1.9 Canonical Smiles
- C1=NC(=C2C(=N1)N(C=N2)C3C(C(C(O3)CO)O)O)N
- 1.10 Isomers Smiles
- C1=NC(=C2C(=N1)N(C=N2)[C@H]3[C@H]([C@@H]([C@H](O3)CO)O)O)N
2. Properties
- 2.1 Density
- 2.08
- 2.1 Melting point
- 260-265 °C (dec.)
- 2.1 Boiling point
- 676.3°Cat760mmHg
- 2.1 Refractive index
- 1.907
- 2.1 Flash Point
- 362.8°C
- 2.1 Precise Quality
- 267.09700
- 2.1 PSA
- 139.54000
- 2.1 logP
- -1.39880
- 2.1 Appearance
- OFF-WHITE POWDER
- 2.2 Storage
- Store at -20°C.
- 2.3 Chemical Properties
- Crystalline
- 2.4 Color/Form
- White to Yellow Solid
- 2.5 Decomposition
- When heated to decomposition it emits very toxic fumes of /nitrogen oxides/.
- 2.6 pKa
- pKa 3.55(H2O
t=20
I=0.1 (KCl)) (Uncertain);11.4 (Uncertain)
- 2.7 Water Solubility
- Soluble
- 2.8 Spectral Properties
- Maximum absorption (pH 1): 257.5 nm (E = 12,7000); pH 7: 259 nm (E = 13,400); pH13: 259 nm (E = 14,000).
Specific optical rotation: -5 deg at 27 deg C/D (concentration by volume= 0.25 g in 100 ml water).
- 2.9 StorageTemp
- -20°C
3. Use and Manufacturing
- 3.1 General Description
- Chemically, vidarabine (Vira-A), is 9--D-arabinofuranosyladenine.The drug is the 2'epimer of natural adenosine.Introduced in 1960 as a candidate anticancer agent, vidarabinewas found to have broad-spectrum activity against DNAviruses.The drug is active against herpesviruses,poxviruses, rhabdoviruses, hepadnavirus, and some RNAtumor viruses. Vidarabine was marketed in the United Statesin 1977 as an alternative to idoxuridine for the treatment ofHSV keratitis and HSV encephalitis. Although the agent wasinitially prepared chemically, it is now obtained by fermentationwith strains of Streptomyces antibioticus.The antiviral action of vidarabine is completely confinedto DNA viruses. Vidarabine inhibits viral DNA synthesis.Enzymes within the cell phosphorylate vidarabine to thetriphosphate, which competes with deoxyadenosine triphosphatefor viral DNA polymerase. Vidarabine triphosphate isalso incorporated into cellular and viral DNA, where it actsas a chain terminator. The triphosphate form of vidarabinealso inhibits a set of enzymes that are involved in methylationof uridine to thymidine: ribonucleoside reductase, RNApolyadenylase, and S-adenosylhomocysteine hydrolase.At one time in the United States, intravenous vidarabinewas approved for use against HSV encephalitis, neonatalherpes, and herpes or varicella zoster in immunocompromisedpatients. Acyclovir has supplanted vidarabine as thedrug of choice in these cases.
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- 3.2 Usage
- antifungal;Antiviral;Adenosine antimetabolite.
4. Safety and Handling
- 4.1 Symbol
- GHS08;
- 4.1 Hazard Codes
- Xn
- 4.1 Signal Word
- Warning
- 4.1 Risk Statements
- R63
- 4.1 Safety Statements
- 36/37-36-26
- 4.1 Exposure Standards and Regulations
- Proposed regulation to exempt marketing applications for certain antibiotic drug products, including vidarabine, from regulatory provisions governing marketing exclusivity and patents. [Federal Register: January 24, 2000 (Volume 65, Number 15)]
The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies discontinued drug products. Vidarabine is included on this list.
- 4.2 Packing Group
- II
- 4.2 Octanol/Water Partition Coefficient
- log Kow = -1.11
- 4.3 Fire Hazard
- Flash point data for Vidarabine are not available; however Vidarabine is probably combustible.
- 4.4 Other Preventative Measures
- SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place.
- 4.5 Hazard Class
- 6.1(a)
- 4.5 Hazard Declaration
- H361
- 4.5 DisposalMethods
- SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.
- 4.6 RIDADR
- 2811
- 4.6 Safety Profile
- Poison by ingestion andintravenous routes. Moderately toxic byintraperitoneal route. An experimentalteratogen. Other experimental reproductiveeffects. Human systemic effects byintravenous route: central nervous system,blood, and other effects. A skin and eyeirritant. Human mutation data reported.When heated to decomposition it emitstoxic fumes of NOx.
- 4.7 Caution Statement
- P281
- 4.7 Formulations/Preparations
- Ophthalmic Ointment 3% (equivalent to vidarabine, Vira-A, Parke-Davis anhydrous 2.8%)
Parenteral: Concentrate, for injection, for iv infusion, 200 mg/ml (equivalent to 187.4 mg of anhydrous vidarabine per ml). Vira-A (with benzethonium chloride and phosphate buffers), Parke-Davis
/Vidarabine/ not currently approved for use in the United States
- 4.8 WGK Germany
- 3
- 4.8 RTECS
- AU6200000
- 4.8 Protective Equipment and Clothing
- Burning, itching, and mild irritation of the affected eye are the most common adverse effects of topical vidarabine therapy.
- 4.9 Skin, Eye, and Respiratory Irritations
- Burning, itching, and mild irritation of the affected eye are the most common adverse effects of topical vidarabine therapy.
- 4.10 Safety
- Poison by ingestion and intravenous routes. Moderately toxic by intraperitoneal route. An experimental teratogen. Other experimental reproductive effects. Human systemic effects by intravenous route: central nervous system, blood, and other effects. A skin and eye irritant. Human mutation data reported. When heated to decomposition it emits toxic fumes of NOx.
- 4.11 Specification
-
Crystalline
Safety Statements:36/37-36-26
36/37:Wear suitable protective clothing and gloves
36:Wear suitable protective clothing
26:In case of contact with eyes, rinse immediately with plenty
of water and seek medical advice
- 4.12 Toxicity
-
CHEMICAL IDENTIFICATION
- RTECS NUMBER :
- AU6200000
- CHEMICAL NAME :
- Adenine, 9-beta-D-arabinofuranosyl-
- CAS REGISTRY NUMBER :
- 5536-17-4
- LAST UPDATED :
- 199701
- DATA ITEMS CITED :
- 48
- MOLECULAR FORMULA :
- C10-H13-N5-O4
- MOLECULAR WEIGHT :
- 267.28
- WISWESSER LINE NOTATION :
- T56 BN DN FN HNJ IZ D- ET5OTJ B1Q CQ DQ *D-ARABINO
HEALTH HAZARD DATA
ACUTE TOXICITY DATA
- TYPE OF TEST :
- Standard Draize test
- ROUTE OF EXPOSURE :
- Administration onto the skin
- SPECIES OBSERVED :
- Rodent - rabbit
- TYPE OF TEST :
- Standard Draize test
- ROUTE OF EXPOSURE :
- Administration into the eye
- SPECIES OBSERVED :
- Rodent - rabbit
- TYPE OF TEST :
- Standard Draize test
- ROUTE OF EXPOSURE :
- Administration onto the skin
- SPECIES OBSERVED :
- Rodent - guinea pig
- TYPE OF TEST :
- LDLo - Lowest published lethal dose
- ROUTE OF EXPOSURE :
- Intravenous
- SPECIES OBSERVED :
- Human - woman
- DOSE/DURATION :
- 105 mg/kg/1W-I
- TOXIC EFFECTS :
- Behavioral - hallucinations, distorted perceptions
Behavioral - tremor
- TYPE OF TEST :
- TDLo - Lowest published toxic dose
- ROUTE OF EXPOSURE :
- Intravenous
- SPECIES OBSERVED :
- Human
- DOSE/DURATION :
- 300 ug/kg
- TOXIC EFFECTS :
- Behavioral - anorexia (human)
Gastrointestinal - hypermotility, diarrhea
Nutritional and Gross Metabolic - weight loss or decreased weight gain
- TYPE OF TEST :
- TDLo - Lowest published toxic dose
- ROUTE OF EXPOSURE :
- Intravenous
- SPECIES OBSERVED :
- Human
- DOSE/DURATION :
- 2 mg/kg
- TOXIC EFFECTS :
- Brain and Coverings - changes in surface EEG
Behavioral - toxic psychosis
Behavioral - ataxia
- TYPE OF TEST :
- LD50 - Lethal dose, 50 percent kill
- ROUTE OF EXPOSURE :
- Oral
- SPECIES OBSERVED :
- Rodent - rat
- DOSE/DURATION :
- >5 gm/kg
- TOXIC EFFECTS :
- Liver - other changes
- TYPE OF TEST :
- LD50 - Lethal dose, 50 percent kill
- ROUTE OF EXPOSURE :
- Intraperitoneal
- SPECIES OBSERVED :
- Rodent - rat
- DOSE/DURATION :
- 1476 mg/kg
- TOXIC EFFECTS :
- Details of toxic effects not reported other than lethal dose value
- TYPE OF TEST :
- LD50 - Lethal dose, 50 percent kill
- ROUTE OF EXPOSURE :
- Subcutaneous
- SPECIES OBSERVED :
- Rodent - rat
- DOSE/DURATION :
- 8914 mg/kg
- TOXIC EFFECTS :
- Details of toxic effects not reported other than lethal dose value
- TYPE OF TEST :
- LD50 - Lethal dose, 50 percent kill
- ROUTE OF EXPOSURE :
- Intravenous
- SPECIES OBSERVED :
- Rodent - rat
- DOSE/DURATION :
- 302 mg/kg
- TOXIC EFFECTS :
- Details of toxic effects not reported other than lethal dose value
- TYPE OF TEST :
- LD50 - Lethal dose, 50 percent kill
- ROUTE OF EXPOSURE :
- Oral
- SPECIES OBSERVED :
- Rodent - mouse
- DOSE/DURATION :
- 7800 ug/kg
- TOXIC EFFECTS :
- Details of toxic effects not reported other than lethal dose value
- TYPE OF TEST :
- LD50 - Lethal dose, 50 percent kill
- ROUTE OF EXPOSURE :
- Intraperitoneal
- SPECIES OBSERVED :
- Rodent - mouse
- DOSE/DURATION :
- 3057 mg/kg
- TOXIC EFFECTS :
- Details of toxic effects not reported other than lethal dose value
- TYPE OF TEST :
- LD50 - Lethal dose, 50 percent kill
- ROUTE OF EXPOSURE :
- Subcutaneous
- SPECIES OBSERVED :
- Rodent - mouse
- DOSE/DURATION :
- 5086 mg/kg
- TOXIC EFFECTS :
- Details of toxic effects not reported other than lethal dose value
- TYPE OF TEST :
- LD50 - Lethal dose, 50 percent kill
- ROUTE OF EXPOSURE :
- Intravenous
- SPECIES OBSERVED :
- Rodent - mouse
- DOSE/DURATION :
- 442 mg/kg
- TOXIC EFFECTS :
- Details of toxic effects not reported other than lethal dose value
- TYPE OF TEST :
- TDLo - Lowest published toxic dose
- ROUTE OF EXPOSURE :
- Intramuscular
- SPECIES OBSERVED :
- Rodent - rat
- DOSE/DURATION :
- 4200 mg/kg/28D-I
- TOXIC EFFECTS :
- Skin and Appendages - dermatitis, other (after systemic exposure)
Nutritional and Gross Metabolic - weight loss or decreased weight gain
- TYPE OF TEST :
- TDLo - Lowest published toxic dose
- ROUTE OF EXPOSURE :
- Oral
- SPECIES OBSERVED :
- Rodent - mouse
- DOSE/DURATION :
- 61600 mg/kg/4W-I
- TOXIC EFFECTS :
- Behavioral - muscle weakness
Liver - other changes
Nutritional and Gross Metabolic - weight loss or decreased weight gain
- TYPE OF TEST :
- TDLo - Lowest published toxic dose
- ROUTE OF EXPOSURE :
- Intramuscular
- SPECIES OBSERVED :
- Mammal - dog
- DOSE/DURATION :
- 1400 mg/kg/28D-I
- TOXIC EFFECTS :
- Skin and Appendages - dermatitis, other (after systemic exposure)
- TYPE OF TEST :
- TDLo - Lowest published toxic dose
- ROUTE OF EXPOSURE :
- Intramuscular
- SPECIES OBSERVED :
- Primate - monkey
- DOSE/DURATION :
- 2100 mg/kg/28D-I
- TOXIC EFFECTS :
- Sense Organs and Special Senses (Eye) - visual field changes
Behavioral - tremor
Behavioral - muscle weakness
- TYPE OF TEST :
- TDLo - Lowest published toxic dose
- ROUTE OF EXPOSURE :
- Intramuscular
- DOSE :
- 2 gm/kg
- SEX/DURATION :
- female 6-15 day(s) after conception
- TOXIC EFFECTS :
- Reproductive - Specific Developmental Abnormalities - craniofacial
(including nose and tongue)
Reproductive - Specific Developmental Abnormalities - urogenital system
Reproductive - Specific Developmental Abnormalities - musculoskeletal system
- TYPE OF TEST :
- TDLo - Lowest published toxic dose
- ROUTE OF EXPOSURE :
- Intramuscular
- DOSE :
- 2 gm/kg
- SEX/DURATION :
- female 6-15 day(s) after conception
- TOXIC EFFECTS :
- Reproductive - Fertility - post-implantation mortality (e.g. dead and/or
resorbed implants per total number of implants)
Reproductive - Effects on Embryo or Fetus - fetotoxicity (except death,
e.g., stunted fetus)
- TYPE OF TEST :
- TDLo - Lowest published toxic dose
- ROUTE OF EXPOSURE :
- Intramuscular
- DOSE :
- 2500 mg/kg
- SEX/DURATION :
- female 6-15 day(s) after conception
- TOXIC EFFECTS :
- Reproductive - Specific Developmental Abnormalities - Central Nervous System
Reproductive - Specific Developmental Abnormalities - eye/ear
Reproductive - Specific Developmental Abnormalities - body wall
- TYPE OF TEST :
- TDLo - Lowest published toxic dose
- ROUTE OF EXPOSURE :
- Intramuscular
- DOSE :
- 2500 mg/kg
- SEX/DURATION :
- female 6-15 day(s) after conception
- TOXIC EFFECTS :
- Reproductive - Fertility - litter size (e.g. # fetuses per litter; measured
before birth)
Reproductive - Fertility - pre-implantation mortality (e.g. reduction in
number of implants per female; total number of implants per corpora lutea)
- TYPE OF TEST :
- TDLo - Lowest published toxic dose
- ROUTE OF EXPOSURE :
- Intravaginal
- DOSE :
- 1316 mg/kg
- SEX/DURATION :
- female 15-21 day(s) after conception
- TOXIC EFFECTS :
- Reproductive - Fertility - litter size (e.g. # fetuses per litter; measured
before birth)
- TYPE OF TEST :
- TDLo - Lowest published toxic dose
- ROUTE OF EXPOSURE :
- Administration onto the skin
- DOSE :
- 2613 mg/kg
- SEX/DURATION :
- female 6-18 day(s) after conception
- TOXIC EFFECTS :
- Reproductive - Effects on Embryo or Fetus - fetotoxicity (except death,
e.g., stunted fetus)
Reproductive - Fertility - litter size (e.g. # fetuses per litter; measured
before birth)
Reproductive - Specific Developmental Abnormalities - musculoskeletal system
- TYPE OF TEST :
- TDLo - Lowest published toxic dose
- ROUTE OF EXPOSURE :
- Administration onto the skin
- DOSE :
- 2613 mg/kg
- SEX/DURATION :
- female 6-18 day(s) after conception
- TOXIC EFFECTS :
- Reproductive - Specific Developmental Abnormalities - respiratory system
Reproductive - Specific Developmental Abnormalities - craniofacial
(including nose and tongue)
- TYPE OF TEST :
- TDLo - Lowest published toxic dose
- ROUTE OF EXPOSURE :
- Administration onto the skin
- DOSE :
- 260 mg/kg
- SEX/DURATION :
- female 6-18 day(s) after conception
- TOXIC EFFECTS :
- Reproductive - Fertility - post-implantation mortality (e.g. dead and/or
resorbed implants per total number of implants)
- TYPE OF TEST :
- TDLo - Lowest published toxic dose
- ROUTE OF EXPOSURE :
- Intramuscular
- DOSE :
- 13 mg/kg
- SEX/DURATION :
- female 6-18 day(s) after conception
- TOXIC EFFECTS :
- Reproductive - Specific Developmental Abnormalities - musculoskeletal system
- TYPE OF TEST :
- Cytogenetic analysis
MUTATION DATA
- TYPE OF TEST :
- Cytogenetic analysis
- TEST SYSTEM :
- Mammal - species unspecified Cells - not otherwise
specified
- DOSE/DURATION :
- 1 mmol/L
- REFERENCE :
- MUREAV Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE
Amsterdam, Netherlands) V.1- 1964- Volume(issue)/page/year: 120,139,1983
*** NIOSH STANDARDS DEVELOPMENT AND SURVEILLANCE DATA ***
NIOSH OCCUPATIONAL EXPOSURE SURVEY DATA :
NOES - National Occupational Exposure Survey (1983)
NOES Hazard Code - X5559
No. of Facilities: 26 (estimated)
No. of Industries: 1
No. of Occupations: 2
No. of Employees: 1307 (estimated)
No. of Female Employees: 664 (estimated)
- View all
5. MSDS
2.Hazard identification
2.1 Classification of the substance or mixture
Reproductive toxicity, Category 2
2.2 GHS label elements, including precautionary statements
| Pictogram(s) |  |
| Signal word | Warning |
| Hazard statement(s) | H361 Suspected of damaging fertility or the unborn child |
| Precautionary statement(s) | |
| Prevention | P201 Obtain special instructions before use. P202 Do not handle until all safety precautions have been read and understood. P280 Wear protective gloves/protective clothing/eye protection/face protection. |
| Response | P308+P313 IF exposed or concerned: Get medical advice/ attention. |
| Storage | P405 Store locked up. |
| Disposal | P501 Dispose of contents/container to ... |
2.3 Other hazards which do not result in classification
none
7. Synthesis Route
5536-17-4Total: 30 Synthesis Route
9. Other Information
- 9.0 Merck
- 13,10039
- 9.1 BRN
- 624881
- 9.2 Description
- Vidarabine (adenine arabinoside) is the stereoisomer of adenosine. This analog of a purine nucleoside exhibits selective activity against the herpes virus. The ribose residue is replaced with an arabinose residue. Like acyclovir, it turns into mono-, di-, and triphosphate in cells infected by a virus, thus inhibiting DNA polymerase, and correspondingly preventing DNA synthesis of the virus approximately 20–40 times more than in “host” cells. It is easily metabolized to a less active, yet nonetheless antiviral compound—arabinosylhypoxanthine. It has been successfully used for herpetic encephalitis, and for complicated shingles. It is used in the form of eye drops for herpetic keratoconjuctivitis. A synonym of this drug is Vira-A.
- 9.3 Description
- Vidarabine is an analog of the nucleoside adenosine that has antiviral properties. It acts as a prodrug that, once phosphorylated by cellular enzymes, acts as both substrate and inhibitor of DNA polymerase.1 Vidarabine is particularly effective against H. simplex and V. zoster viruses.1
- 9.4 Chemical Properties
- Crystalline
- 9.5 Originator
- Vidarabin ,Thilo,W. Germany ,1975
- 9.6 Uses
- antifungal;Antiviral;Adenosine antimetabolite.
- 9.7 Uses
- active component of chili peppers, analgesic and therapeutic agent for arthritis, potential prophylactic for type 1 diabetes
- 9.8 Uses
- Vidarabine, is an antiviral drug which is active against herpes simplex and varicella zoster viruses.
- 9.9 Indications
- Vidarabine (adenine arabinoside, Vira-A) is an adenine nucleoside analogue containing arabinose in place of ribose. It is obtained from cultures of Streptomyces antibioticus and has activity against HSV-1, HSV-2, VZV, CMV, HBV, poxviruses, hepadnaviruses, rhabdoviruses, and certain RNA tumor viruses.
- 9.10 Manufacturing Process
- Sterile agar slants are prepared using the Streptomyces sporulation medium of Hickey and Tresner, J. Bact., vol. 64, pages 891-892 (1952). Four of these slants are inoculated with lyophilized spores of Streptomyces antibioticus NRRL 3238, incubated at 28°C for 7 days or until aerial spore growth is well- advanced, and then stored at 5°C. The spores from the four slants are suspended in 40 ml of 0.1% sterile sodium heptadecyl sulfate solution. A nutrient medium having the following composition is then prepared: 2.0% glucose monohydrate; 1.0% soybean meal, solvent extracted, 44% protein; 0.5% animal peptone (Wilson's protopeptone 159); 0.2% ammonium chloride; 0.5% sodium chloride; 0.25% calcium carbonate; and water to make 100%.
The pH of the medium is adjusted with 10-normal sodium hydroxide solution to pH 7.5. 12 liters of this medium is placed in a 30-liter stainless steel fermenter. The medium is sterilized by heating it at 121°C for 90 minutes, allowed to cool, inoculated with the 40 ml spore suspension described above, and incubated at 25° to 27°C for 32 hours while being agitated at 200 rpm with air being supplied at the rate of 12 liters per minute. About 38 grams of a mixture of lard and mineral oils containing mono-and diglycerides is added in portions during this time to prevent excessive foaming.
16 liters of a nutrient medium having the composition described above is placed in each of four 30-liter stainless steel fermenters. The pH of the medium in each fermenter is adjusted with 10-normal sodium hydroxide solution to pH 7.5, and each is sterilized by heating at 121°C for 90 minutes. Upon cooling, the medium in each fermenter is inoculated with 800 ml of the fermentation mixture described above, and each is incubated at 25° to 27°C for 96 hours while being agitated at 200 rpm with air being supplied at the rate of 16 liters per minute. About 170 grams of the antifoam mixture described above is added in portions during this time to the medium in each fermenter.
The fermentation mixtures from the four fermenters are combined and filtered with the aid of diatomaceous earth, A material such as Celite 545 can be used. The filtrate is concentrated under reduced pressure to a volume of 10 liters, and the concentrate is treated with 200 grams of activated charcoal (for example, Darco G-60), stirred at room temperature for one hour, and filtered. The charcoal cake is washed with 7.5 liters of water, and then extracted with three 10-liter portions of 50% aqueous acetone. The three aqueous acetone extracts are combined, concentrated under reduced pressure to approximately one liter, and chilled at 5°C for 48 hours. The solid 9-(β-D- arabinofuranosyl)adenine that precipitates is isolated and purified by successive crystallizations from boiling methanol and from boiling water; MP 262° to 263°C.
In the foregoing procedure, when the temperature of incubation in the two fermentation stages is raised from 25° to 27°C to 36° to 38°C, the same 9- (β-D-arabinofuranosyl)adenine product is obtained in higher yields. - View all
- 9.11 Brand name
- Vira-A (Parkdale).
- 9.12 Therapeutic Function
- Antiviral
- 9.13 General Description
- Chemically, vidarabine (Vira-A), is 9--D-arabinofuranosyladenine.The drug is the 2'epimer of natural adenosine.Introduced in 1960 as a candidate anticancer agent, vidarabinewas found to have broad-spectrum activity against DNAviruses.The drug is active against herpesviruses,poxviruses, rhabdoviruses, hepadnavirus, and some RNAtumor viruses. Vidarabine was marketed in the United Statesin 1977 as an alternative to idoxuridine for the treatment ofHSV keratitis and HSV encephalitis. Although the agent wasinitially prepared chemically, it is now obtained by fermentationwith strains of Streptomyces antibioticus.
The antiviral action of vidarabine is completely confinedto DNA viruses. Vidarabine inhibits viral DNA synthesis.Enzymes within the cell phosphorylate vidarabine to thetriphosphate, which competes with deoxyadenosine triphosphatefor viral DNA polymerase. Vidarabine triphosphate isalso incorporated into cellular and viral DNA, where it actsas a chain terminator. The triphosphate form of vidarabinealso inhibits a set of enzymes that are involved in methylationof uridine to thymidine: ribonucleoside reductase, RNApolyadenylase, and S-adenosylhomocysteine hydrolase.
At one time in the United States, intravenous vidarabinewas approved for use against HSV encephalitis, neonatalherpes, and herpes or varicella zoster in immunocompromisedpatients. Acyclovir has supplanted vidarabine as thedrug of choice in these cases. - View all
- 9.14 General Description
- White to off-white crystalline powder.
- 9.15 Air & Water Reactions
- Insoluble in water.
- 9.16 Reactivity Profile
- Vidarabine is an aminoalcohol. Amines are chemical bases. They neutralize acids to form salts plus water. These acid-base reactions are exothermic. The amount of heat that is evolved per mole of amine in a neutralization is largely independent of the strength of the amine as a base. Amines may be incompatible with isocyanates, halogenated organics, peroxides, phenols (acidic), epoxides, anhydrides, and acid halides. Flammable gaseous hydrogen is generated by amines in combination with strong reducing agents, such as hydrides.
- 9.17 Fire Hazard
- Flash point data for Vidarabine are not available; however Vidarabine is probably combustible.
- 9.18 Usage
- Vidarabine is a neurotransmitter that acts as the preferred endogenous agonist at all adenosine receptor subtypes. Vidarabine is an inhibitor of A cyclase and DNA Polymerase. Used to study the roles of AMP-activated protein kinase (AMPK) in cell signaling. Cell-permeable adenylate cyclase inhibitor; in detergent-dispersed rat brain preparation, IC50 = 30 ?M. Clinically significant antiviral agent, especially against herpes simplex (HSV),1 by inhibition of DNA polymerase.
- 9.19 Biochem/physiol Actions
- Cell-permeable adenylate cyclase inhibitor; in detergent-dispersed rat brain preparation, IC50 = 30 μM. Clinically significant antiviral agent, especially against herpes simplex (HSV), by inhibition of DNA polymerase.
- 9.20 Mechanism of action
- Vidarabine’s specific mechanism of action is not fully understood. Cellular enzymes convert this drug to a triphosphate that inhibits DNA polymerase activity. Vidarabine triphosphate competes with deoxyadenosine triphosphate (dATP) for access to DNA polymerase and also acts as a chain terminator. Although vidarabine is incorporated into host DNA to some extent, viral DNA polymerase is much more susceptible to inhibition by vidarabine. Vidarabine also inhibits ribonucleoside reductase and other enzymes. Resistance occurs as a result of DNA polymerase mutation.
- 9.21 Pharmacokinetics
- Vidarabine is deaminated rapidly by adenosine deaminase, which is present in serum and red blood cells. The enzyme converts vidarabine to its principal metabolite, arabinosyl hypoxanthine (ara-HX), which has weak antiviral activity. The half-life of vidarabine is approximately 1 hour, whereas ara-HX has a half-life of 3.5 hours. The drug is detected mostly in the kidney, liver, and spleen, because 50% of it is recovered in the urine as ara-HX. Levels of vidarabine in CSF fluid are 50% of those in the plasma.
- 9.22 Clinical Use
- The principal use of vidarabine is in the treatment of HSV keratoconjunctivitis. It is also used to treat superficial keratitis in patients unresponsive or hypersensitive to topical idoxuridine.
- 9.23 Side effects
- The most commonly observed side effects associated with vidarabine are lacrimation, burning, irritation, pain, and photophobia. Vidarabine has oncogenic and mutagenic potential; however, the risk of systemic effects is low because of its limited absorption. It should not be used in conjunction with ophthalmic corticosteroids, since these drugs increase the spread of HSV infection and may produce side effects such as increased intraocular pressure, glaucoma, and cataracts.
- 9.24 Safety Profile
- Poison by ingestion and intravenous routes. Moderately toxic by intraperitoneal route. An experimental teratogen. Other experimental reproductive effects. Human systemic effects by intravenous route: central nervous system, blood, and other effects. A skin and eye irritant. Human mutation data reported. When heated to decomposition it emits toxic fumes of NOx.
- 9.25 Chemical Synthesis
- Vidarabine, 9-B-arabinofuranosyl-6-amino-9-H-pyrine (36.1.10), is synthesized both microbiologically from the culture fluid of the actinomycete Streptomyces antibioticus NRRL 3238, as well as synthetically. It is synthesized from the acetonide-β-D–xylofuranoside of adenine—9-(3,5-O-isopropyliden-β-D–xylofuranoside)adenine, which is reacted with methanesulfonyl chloride to make the mesylate 9-(3,5-O-isopropyliden-2-O-methansulfonyl-β-D-xydlofuranoside)adenine (36.1.7). Prolonged heating in 90% acetic acid removes the acetonyl protective group from the resulting compound, giving the product (36.1.8).
Reacting this with sodium methoxide leads to the formation of an epoxide— 9-(2,3-anhydro-β-luxofuranosyl)adenine (36.1.9). Finally, heating this epoxide with sodium acetate or benzoate opens the epoxide ring in the dimethylformamide–water system to make the corresponding dihydroxy derivative, vidarabine.
Another way of synthesis of vidarabine that was developed later consists of alkylating of 6-benzamidopurine with 2,3,5-tri-O-benzyl-D-arabinofuranosyl chloride using sodium in liquid ammonia. This simultaneously N-debenzylates the sixth position of the purine system and fulfil O-debenzylation of hydroxyl groups of the furanosyl fragment of the molucule, giving vidarabine.
- View all
10. Computational chemical data
- Molecular Weight: 267.24132g/mol
- Molecular Formula: C10H13N5O4
- Compound Is Canonicalized: True
- XLogP3-AA: null
- Exact Mass: 267.09675391
- Monoisotopic Mass: 267.09675391
- Complexity: 335
- Rotatable Bond Count: 2
- Hydrogen Bond Donor Count: 4
- Hydrogen Bond Acceptor Count: 8
- Topological Polar Surface Area: 140
- Heavy Atom Count: 19
- Defined Atom Stereocenter Count: 4
- Undefined Atom Stereocenter Count: 0
- Defined Bond Stereocenter Count: 0
- Undefined Bond Stereocenter Count: 0
- Isotope Atom Count: 0
- Covalently-Bonded Unit Count: 1
- CACTVS Substructure Key Fingerprint: AAADccBzuAAAAAAAAAAAAAAAAAAAAWJAAAAsAAAAAAAAAFgB+AAAHgAQCAAACBzhlwYF8L9MFgCgAQZhZACAgC0REKABUCAoVBCDWAJAyEAeRAgPAALTACDwMAIAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA==
11. Question & Answer
-
Vidarabine, also known as adenine arabinoside or Ara-A, is a purine analog that effectively inhibits the replication of various DNA and oncogenic RNA viruses. Originally developed as an anti-cancer ag..
-
Vidarabine is an antiviral drug commonly used in clinical practice, especially its phosphate ester - Vidarabine monophosphate for injection. Vidarabine is currently one of the most widely used antivir..
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