5536-17-4

Usage

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.

Upstream product

• 3257-73-6 9-(2',3',5'-tri-O-benzyl-β-D-arabinofuranosyl)adenine 
• 65174-95-0 9-(2-O-acetyl-β-D-arabinofuranosyl)adenine 
• 65286-65-9 9-<3-O-acetyl-β-D-arabinofuranosyl>adenine 
• 69304-45-6 3',5'-O-(1,1,3,3-tetra-isopropyldisiloxane-1,3-diyl)adenosine 
• 3083-77-0 araU 
• 66224-66-6 adenine 
• 362-75-4 2',3'-isopropylidene adenosine 
• 2391-46-0 ara-ApA 
• 81841-70-5 ara-ApApA 
• 634-01-5 adenosine 2',3'-cyclic monophosphate 
• 76054-92-7 5-amino-1-(β-D-arabinofuranosyl)-4-cyanoimidazole 
• 122-51-0 orthoformic acid triethyl ester 
• 65926-28-5 9-(5-O-acetyl-β-D-arabinofuranosyl)adenine 
• 62374-24-7 (2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-2-((benzoyloxy)methyl)-4-hydroxytetrahydrofuran-3-yl benzoate 

Downstream Products

• 1040031-35-3 9-[5'-O-(tert-butyldiphenylsilyl)-β-D-arabinofuranosyl]adenine 
• 3714-60-1 2'-9β-D-arabinofuranosyladenine 5'-triphosphate 
• 65446-56-2 2'-Br-dA 
• 68775-04-2 2'-deoxy-2'-iodoadenosine 
• 67313-23-9 3',5'-Diamino-3',5'-dideoxyadenosine 
• 183059-49-6 2-[(2R,3R,4R,5R)-5-(6-Amino-purin-9-yl)-3-azido-4-benzyloxy-tetrahydro-furan-2-ylmethyl]-isoindole-1,3-dione 
• 93488-74-5 Benzoic acid (2R,3S,4R,5R)-2-(6-benzoylamino-purin-9-yl)-4-hydroxy-5-hydroxymethyl-tetrahydro-furan-3-yl ester 
• 82144-92-1 N-benzoyl-3',5'-O-bis-monomethoxytritylarabinosyladenine 
• 82144-93-2 N⁶-benzoyl-9-<2,5-di-O-(4-monomethoxytrityl)-β-D-arabinofuranosyl>adenine 
• 82144-94-3 N,2'-O-dibenzoyl-3',5'-O-bis-monomethoxytrityl arabinosyladenine 
• 82144-95-4 Benzoic acid (2R,3R,4S,5R)-5-(6-benzoylamino-purin-9-yl)-4-[(4-methoxy-phenyl)-diphenyl-methoxy]-2-[(4-methoxy-phenyl)-diphenyl-methoxymethyl]-tetrahydro-furan-3-yl ester 
• 82144-96-5 5'-O-dimethoxytrityl-N,2'-O-dibenzoylarabinosyladenine 
• 58699-61-9 2'-Azido-2'-deoxyadenosine 
• 127246-67-7 2',3'-di-O-p-tolylsulphonyl-9-β-D-arabinofuranosyladenine 

Relevant academic research and scientific papers

An enzymatic flow-based preparative route to vidarabine

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

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.

Production process of arabinoside

The invention discloses a production process of arabinoside, relates to the technical field of arabinoside synthesis, and solves the technical problems that in the existing production process of arabinoside, after-treatment of an acetic acid buffer agent reaction solution is difficult, a 1, 2-dichloroethane solvent is difficult to recover, potassium permanganate is slow to charge, and the reactiontime is too long. The production process of arabinoside comprises the following steps: synthesis of 8-bromoadenosine, synthesis of 8-bromo-2'-O-p-toluenesulfonyl adenosine, synthesis of 8-hydroxy-4'-acetoxy-5'-acetoxymethyl-3'-p-toluenesulfonyl adenosine and synthesis of arabinoside. In the production process of arabinoside, after-treatment of wastewater is convenient, hazardous waste is convenient to treat, the process cost is low, and the reaction time is short.

A method for synthesizing arabinosyladenosine (by machine translation)

The invention discloses a method for synthesizing arabinosyladenosine method, which belongs to the field of nucleoside in organic chemistry synthesis. The reaction steps are as follows: in order to adenosine as raw material, in a catalytic amount of dibutyl tin oxide or borate and under the action of the nitrobenzene sulfonyl chloride reaction, to obtain the 2 '- to the nitrobenzene sulfonyl protecting adenosine, then under the action of the potassium acetate and catalyst, undergo the substitution reaction to obtain the 2' - acetyl arabinosyladenosine, finally ammonolysis to obtain arabinosyladenosine. The synthesis method cheap raw materials, the step is short, easy to industrial production, with the actual application prospect. (by machine translation)

Enzymatic Synthesis of Therapeutic Nucleosides using a Highly Versatile Purine Nucleoside 2’-DeoxyribosylTransferase from Trypanosoma brucei

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.

Vidarabine synthesis method

The invention relates to a vidarabine synthesis method. The method comprises the steps that 8-hydroxy-N,3',5'-O-triethyl-2'-O-p-tosyl adenosine is added, hydrazine hydrate with the mass time being 1.1-1.4 and the mass percent being 80% is added, heating is conducted to reach 78-85 DEG C, and a thermal reaction is conducted for 45-50 h; distillation is conducted under pressure reduction, and the hydrazine hydrate is removed; the original raw materials of water with the mass time being 5-8 and catalytic oxidizer potassium permanganate with the mass time being 0.03-0.12 are added, a stirring reaction is conducted at the room temperature for 6-8 h, a solid obtained after reaction liquid is filtered is a vidarabine crude product; the crude product is subjected to actived carbon decoloration andrecrystallization in sequence, and a vidarabine pure product is obtained. Accordingly, a cascade reaction is conducted through a one-pot two-step method, overturning and deprotection of configurationare completed through a hydrazine hydrate one pot method, the configuration overturning purpose is achieved by replacing two reactions of methanol ammonia system cyclization and hydrogen sulfide system hydrogenation ring opening, and meanwhile an inflammable catalyst raney nickel dehydroxyl is avoided, and the safety of the overall reaction is improved. Dehydrazination is conducted with potassiumpermanganate, the activity of the reaction is improved, and the content of heavy metal in waste water is lowered.

Synthesis of Adenine Nucleosides by Transglycosylation using Two Sequential Nucleoside Phosphorylase-Based Bioreactors with On-Line Reaction Monitoring by using HPLC

Uridine phosphorylase from Clostridium perfringens (CpUP, EC 2.4.2.3) was immobilized covalently in an aminopropylsilica monolithic column (25 mm×4.6 mm) upon functionalization with glutaraldehyde. Imino bonds that result from the reaction between the enzyme and the support were reduced chemically to afford a 66 % yield (13 mg) determined spectrophotometrically. The CpUP immobilized enzyme reactor (IMER) was connected to a silica particle-based IMER that contained a purine nucleoside phosphorylase from Aeromonas hydrophila (AhPNP, EC 2.4.2.1), which was developed previously and used successfully for the fast synthesis of some purine ribonucleosides by a “one-enzyme” transglycosylation. CpUP-IMER and AhPNP-IMER were connected to a HPLC system by a six-way switching valve. In this set-up, the synthesis of 2′-deoxyadenosine (dAdo, 8), adenosine (Ado, 9), and arabinosyladenine (araA, 10) by a “two-enzyme” transglycosylation is coupled directly to on-line reaction monitoring. Under the optimized transglycosylation conditions (2:1 ratio sugar donor/base acceptor; 10 mm phosphate buffer; pH 7.25; temperature 37 °C, flow rate 0.1 mL min?1), defined by a 2(5-2) III experimental design, the conversion of dAdo and Ado was approximately 90 %, and araA was synthesized in 20 % yield.

The arsenolysis reaction in the biotechnological method of synthesis of modified purine β-D-arabinonucleosides

We found a unique property of E. coli purine nucleoside phosphorylases to selectively perform the arsenolysis reaction of ribonucleosides in their active site without affecting β-D-arabinonucleosides. In the synthesis of modified β-D-arabinonucleosides from the corresponding ribonucleosides, the catalytical amount of sodium arsenate in the transglycosylation reaction provided a 95 to 98% conversion rate. Such an approach was shown to simplify the composition of the reaction mixtures and facilitate the isolation of the target nucleosides, particularly, vidarabine, fludarabine, and nelarabine.

Redesigning the synthesis of vidarabine via a multienzymatic reaction catalyzed by immobilized nucleoside phosphorylases

We here report on the enzymatic synthesis of the antiviral drug vidarabine (arabinosyladenine, araA) starting from arabinosyluracil and adenine. To this aim, uridine phosphorylase from Clostridium perfringens (CpUP) and a purine nucleoside phosphorylase from Aeromonas hydrophila (AhPNP) were used as covalently immobilized biocatalysts. Upon investigation of the optimal conditions for the enzyme activity (phosphate buffer 25 mM, pH 7.5, 25 °C, DMF 12.5-30%), the synthesis of araA was scaled up (2 L) and the product was isolated in 53% yield (3.5 g L-1) and 98.7% purity. An E-factor comparison between the enzymatic synthesis of araA and the classical chemical procedure clearly highlighted the greenness of the enzymatic route over the chemical one (E-factor: 423 vs. 1356, respectively). copy; The Royal Society of Chemistry 2015.

Efficient synthesis of nebularine and vidarabine via dehydrazination of (hetero)aromatics catalyzed by CuSO4 in water

A simple dehydrazination reaction has been achieved in the presence of a catalytic amount of CuSO4 for the first time. With CuSO4 (2 mol%) as a catalyst and water as a solvent, the dehydrazination products were obtained in good yields (66-95%). Moreover, the drugs nebularine and vidarabine were afforded successfully, and vidarabine could be produced on a 0.923 kg scale, which shows good potential for industrial applications.