5536-17-4 Usage
Description
Vidarabine, also known as adenine arabinoside or Vira-A, is a synthetic nucleoside analog of adenosine with antiviral properties. It is chemically defined as 9-β-D-arabinofuranosyladenine and is the 2'epimer of natural adenosine. Initially introduced as a candidate anticancer agent in 1960, vidarabine was found to have broad-spectrum activity against DNA viruses. The drug is particularly effective against herpesviruses, poxviruses, rhabdoviruses, hepadnavirus, and some RNA tumor viruses. It is a crystalline compound that has been used to treat various viral infections.
Uses
Used in Antiviral Applications:
Vidarabine is used as an antiviral drug for the treatment of herpes simplex and varicella zoster viruses. It acts as a prodrug that, once phosphorylated by cellular enzymes, acts as both a substrate and inhibitor of DNA polymerase, thereby inhibiting viral DNA synthesis. Vidarabine is particularly effective against H. simplex and V. zoster viruses.
Used in Herpetic Encephalitis Treatment:
Vidarabine is used as an antiviral agent for the treatment of herpetic encephalitis, a potentially life-threatening condition caused by herpes simplex virus infection of the brain.
Used in Complicated Shingles Treatment:
Vidarabine is used as a therapeutic agent for complicated shingles, a painful rash caused by the reactivation of the varicella-zoster virus.
Used in Ophthalmology:
Vidarabine is used in the form of eye drops for the treatment of herpetic keratoconjunctivitis, an infection of the cornea and conjunctiva caused by the herpes simplex virus.
Used in Antifungal Applications:
Although not explicitly mentioned in the provided materials, vidarabine may also have potential applications in antifungal treatments due to its broad-spectrum activity against various viruses.
Used in Arthritis Treatment:
Vidarabine is used as an analgesic and therapeutic agent for arthritis, potentially providing relief from pain and inflammation associated with the condition.
Used in Type 1 Diabetes Prophylaxis:
Vidarabine has been identified as a potential prophylactic for type 1 diabetes, possibly helping to prevent or delay the onset of the disease.
Used in the Active Component of Chili Peppers:
Vidarabine is used as an active component in chili peppers, contributing to their characteristic heat and potentially providing some of the health benefits associated with their consumption.
Originator
Vidarabin ,Thilo,W. Germany ,1975
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.
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.
Therapeutic Function
Antiviral
Air & Water Reactions
Insoluble in water.
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.
Fire Hazard
Flash point data for Vidarabine are not available; however Vidarabine is probably combustible.
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.
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.
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.
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.
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.
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.
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.
Check Digit Verification of cas no
The CAS Registry Mumber 5536-17-4 includes 7 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 4 digits, 5,5,3 and 6 respectively; the second part has 2 digits, 1 and 7 respectively.
Calculate Digit Verification of CAS Registry Number 5536-17:
(6*5)+(5*5)+(4*3)+(3*6)+(2*1)+(1*7)=94
94 % 10 = 4
So 5536-17-4 is a valid CAS Registry Number.
5536-17-4Relevant articles and documents
An enzymatic flow-based preparative route to vidarabine
Annunziata, Francesca,Bavaro, Teodora,Calleri, Enrica,Conti, Paola,Pinto, Andrea,Previtali, Clelia,Rinaldi, Francesca,Speranza, Giovanna,Tamborini, Lucia,Terreni, Marco,Ubiali, Daniela
, (2020)
The bi-enzymatic synthesis of the antiviral drug vidarabine (arabinosyladenine, ara-A), catalyzed by uridine phosphorylase from Clostridium perfringens (CpUP) and a purine nucleoside phosphorylase fromAeromonas hydrophila (AhPNP), was re-designed under continuous-flow conditions. Glyoxyl-agarose and EziGTM1 (Opal) were used as immobilization carriers for carrying out this preparative biotransformation. Upon setting-up reaction parameters (substrate concentration and molar ratio, temperature, pressure, residence time), 1 g of vidarabine was obtained in 55% isolated yield and >99% purity by simply running the flow reactor for 1 week and then collecting (by filtration) the nucleoside precipitated out of the exiting flow. Taking into account the substrate specificity of CpUP and AhPNP, the results obtained pave the way to the use of the CpUP/AhPNP-based bioreactor for the preparation of other purine nucleosides.
Prebiotic Photochemical Coproduction of Purine Ribo- And Deoxyribonucleosides
Xu, Jianfeng,Green, Nicholas J.,Russell, David A.,Liu, Ziwei,Sutherland, John D.
supporting information, p. 14482 - 14486 (2021/09/18)
The hypothesis that life on Earth may have started with a heterogeneous nucleic acid genetic system including both RNA and DNA has attracted broad interest. The recent finding that two RNA subunits (cytidine, C, and uridine, U) and two DNA subunits (deoxyadenosine, dA, and deoxyinosine, dI) can be coproduced in the same reaction network, compatible with a consistent geological scenario, supports this theory. However, a prebiotically plausible synthesis of the missing units (purine ribonucleosides and pyrimidine deoxyribonucleosides) in a unified reaction network remains elusive. Herein, we disclose a strictly stereoselective and furanosyl-selective synthesis of purine ribonucleosides (adenosine, A, and inosine, I) and purine deoxynucleosides (dA and dI), alongside one another, via a key photochemical reaction of thioanhydroadenosine with sulfite in alkaline solution (pH 8-10). Mechanistic studies suggest an unexpected recombination of sulfite and nucleoside alkyl radicals underpins the formation of the ribo C2′-O bond. The coproduction of A, I, dA, and dI from a common intermediate, and under conditions likely to have prevailed in at least some primordial locales, is suggestive of the potential coexistence of RNA and DNA building blocks at the dawn of life.
Enzymatic Synthesis of Therapeutic Nucleosides using a Highly Versatile Purine Nucleoside 2’-DeoxyribosylTransferase from Trypanosoma brucei
Pérez, Elena,Sánchez-Murcia, Pedro A.,Jordaan, Justin,Blanco, María Dolores,Manche?o, José Miguel,Gago, Federico,Fernández-Lucas, Jesús
, p. 4406 - 4416 (2018/09/14)
The use of enzymes for the synthesis of nucleoside analogues offers several advantages over multistep chemical methods, including chemo-, regio- and stereoselectivity as well as milder reaction conditions. Herein, the production, characterization and utilization of a purine nucleoside 2’-deoxyribosyltransferase (PDT) from Trypanosoma brucei are reported. TbPDT is a dimer which displays not only excellent activity and stability over a broad range of temperatures (50–70 °C), pH (4–7) and ionic strength (0–500 mM NaCl) but also an unusual high stability under alkaline conditions (pH 8–10). TbPDT is shown to be proficient in the biosynthesis of numerous therapeutic nucleosides, including didanosine, vidarabine, cladribine, fludarabine and nelarabine. The structure-guided replacement of Val11 with either Ala or Ser resulted in variants with 2.8-fold greater activity. TbPDT was also covalently immobilized on glutaraldehyde-activated magnetic microspheres. MTbPDT3 was selected as the best derivative (4200 IU/g, activity recovery of 22 %), and could be easily recaptured and recycled for >25 reactions with negligible loss of activity. Finally, MTbPDT3 was successfully employed in the expedient synthesis of several nucleoside analogues. Taken together, our results support the notion that TbPDT has good potential as an industrial biocatalyst for the synthesis of a wide range of therapeutic nucleosides through an efficient and environmentally friendly methodology.
Xn:Harmful;
