Vidarabine Chemical Properties

Melting point:

260-265 °C (dec.)

alpha 

D27 -5° (c = 0.25)

Boiling point:

410.43°C (rough estimate)

Density 

1.3382 (rough estimate)

refractive index 

1.7610 (estimate)

storage temp. 

-20°C

solubility 

DMSO (Slightly, Heated)

form 

Powder

pka

pKa 3.55(H2O t=20 I=0.1 (KCl)) (Uncertain);11.4 (Uncertain)

color 

White to Off-white

Water Solubility 

Soluble in DMF (10 mg/ml), 0.5 M HCl (50 mg/ml), DMSO (53 mg/ml at 25°C), ethanol (<1 mg/ml at 25°C), and water (3 mg/ml at 25°C).

Merck 

13,10039

BRN 

624881

InChIKey

OIRDTQYFTABQOQ-UHTZMRCNSA-N

LogP

-0.755 (est)

CAS DataBase Reference

5536-17-4(CAS DataBase Reference)

EPA Substance Registry System

Vidarabine (5536-17-4)

Safety Information

Hazard Codes 

Xn,Xi

Risk Statements 

63-36/37/38

Safety Statements 

36/37-36-26

RIDADR 

2811

WGK Germany 

3

RTECS 

AU6200000

F 

10-23

TSCA 

Yes

HazardClass 

6.1(a)

PackingGroup 

II

HS Code 

29349990

Hazardous Substances Data

5536-17-4(Hazardous Substances Data)

Toxicity

LD50 in mice (mg/kg): 4677 i.p.; >7950 orally (Kurtz)

MSDS

• Language:English Provider:9-beta-D-Arabinosyladenine
• Language:English Provider:SigmaAldrich

Vidarabine Usage And Synthesis

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.

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. Vidarabine is particularly effective against H. simplex and V. zoster viruses.

Chemical Properties

Crystalline

Originator

Vidarabin ,Thilo,W. Germany ,1975

Uses

Vidarabine, is an antiviral drug which is active against herpes simplex and varicella zoster viruses.

Uses

antifungal;Antiviral;Adenosine antimetabolite.

Uses

active component of chili peppers, analgesic and therapeutic agent for arthritis, potential prophylactic for type 1 diabetes

Definition

ChEBI: Adenine arabinoside is a purine nucleoside in which adenine is attached to arabinofuranose via a beta-N(9)-glycosidic bond. It has a role as an antineoplastic agent, a bacterial metabolite and a nucleoside antibiotic. It is a purine nucleoside and a beta-D-arabinoside. It is functionally related to an adenine.

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.

brand name

Vira-A (Parkdale).

Therapeutic Function

Antiviral

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.

General Description

White to off-white crystalline powder.

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.

Vidarabine(5536-17-4)Related Product Information

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