Sunday 31 August 2014

Idoxuridine


 Idoxuridine, NSC-39661, IdUrd, IDUR, IDU, IUDR, Herpid
Idoxuridine is an anti-herpesvirus antiviral drug.
It is a nucleoside analogue, a modified form of deoxyuridine, similar enough to be incorporated into viral DNA replication, but theiodine atom added to the uracil component blocks base pairing. It is used only topically due to cardiotoxicity. It was synthesized byWilliam Prusoff in the late 1950s.[1] Initially developed as an anticancer drug, idoxuridine became the first antiviral agent in 1962.[2]

Clinical use

Idoxuridine is mainly used topically to treat herpes simplex keratitis.[3] Epithelial lesions, especially initial attacks presenting with a dendritic ulcer, are most responsive to therapy, while infection with stromal involvement are less responsive.[4] Idoxuridine is ineffective against herpes simplex virus type 2 and varicella-zoster.[3]

Side effects

Common side effects of the eye drops include irritation, blurred vision and photophobia.[5] Corneal clouding and damage of the corneal epithelium may also occur.[citation needed]

Formulations and dosage

Idoxuridine is available as either a 0.5% ophthalmic ointment or as a 0.1% ophthalmic solution.[3] The dosage of the ointment is every 4 hours during day and once before bedtime.[3] The dosage of the solution is 1 drop in the conjunctival sac hourly during the day and every 2 hours during the night until definitive improvement, then 1 drop every 2 hours during the day and every 4 hours during the night.[3] Therapy is continued for 3-4 days after healing is complete, as demonstrated by fluorescein staining.[3]

UV - spectrum

Conditions : Concentration - 2 mg / 100 ml
SOLVENT DESIGNATION SCHEDULEMETHANOL 
WATER 
0.1 M HCL 
0.1M NAOH 
The absorption maximum284 nm288 nm288 nm280 nm
227217217164
ε8040768076805810

IR - spectrum

WAVELENGTH (ΜM)
WAVENUMBER (CM -1 )

ass Spectrum

SPECTRUM
The 10 largest peaks:
PEAK2839404369112127195238254
MEANING43629139330029531960857099934

Brief background information

SALTATCFORMULAMMCAS
-D06BB01 
J05AB02 
S01AD01
9 H 11 IN 2 O 5354.10 g / mol54-42-2
Idoxuridine
Idoxuridine - Idoxuridin.svg
SYSTEMATIC (IUPAC) NAME
1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-iodo-1,2,3,4-tetrahydropyrimidine-2,4-dione
CLINICAL DATA
AHFS/DRUGS.COMMicromedex Detailed Consumer Information
MEDLINEPLUSa601062
PREGNANCY CAT.(US) B1 (topical), B3 (ophthalmologic) [AU]
LEGAL STATUSPrescription Only (S4) (AU)
ROUTEStopically
IDENTIFIERS
CAS NUMBER54-42-2 Yes
ATC CODED06BB01 J05AB02,S01AD01
PUBCHEMCID 5905
DRUGBANKDB00249
CHEMSPIDER10481938 Yes
UNIILGP81V5245 Yes
KEGGD00342 Yes
CHEMBLCHEMBL788 
NIAID CHEMDB001857
SYNONYMSIododeoxyuridine; IUdR
CHEMICAL DATA
FORMULAC9H11IN2O5 
MOL. MASS354.099 g/mol

Application

  • antiviral ( Herpes simplex )

Classes of substances

  • Iodine compounds
    • Uridine and deoxyuridine

Synthesis pathway

SYNTHESIS A)


SYNTHESIS OF B)


Idoxuridine can be obtained by several related ways: 1) The reaction of 5-iodouracil (I) with refluxing POCl3 and dimethylaniline gives 2,4-dichloro-5-iodopyrimidine (II), which by reaction with NaOCH3 in refluxing methanol, is converted into 2,4-dimethoxy-5-iodopyrimidine (III). The reaction of (III) with 2-deoxy-3,6-di-Op-toluoyl-D-ribofuranosyl chloride (IV) in acetonitrile yields the ribofuranosyl pyridone (V ), which is demethylated with acetic anhydride - dry HCl to afford 2'-deoxy-5-iodo-3 ', 6'-di-Op-toluoyluridine (VI) Finally, this compound is hydrolyzed with NaOCH3 in methanol 2).. The acetylation of 5-iodouracil (I) with refluxing acetic anhydride gives 1-acetyl-5-iodouracil (VII), which by reaction with mercuric acetate in refluxing methanol is converted into the corresponding mercurium salt (VIII). The condensation of (VIII ) with the ribofuranosyl chloride (IV) in chloroform affords the protected 2'-deoxy-5-iodouridine (VI), already obtained. 3) The iodination of 2'-deoxyuridine (IX) with iodine, iodic acid, acetic anhydride, CCl4 and water gives 2'-deoxy-5,6-diiodo-5,6-dihydrouridine (X), which is then treated with NaOH to eliminate HI. 4) By direct iodination of 2'-deoxyuridine (IX) with iodine and nitric acid in refluxing chloroform.
Reference
Cheong, L .; Rich, MA; Eidinoff, ML; Introduction of the 5-halogenated uracil moiety into deoxyribonucleic acid of mammalian cells in culture J Biol Chem 1960, 235, 5, 1441-7.

Trade Names

COUNTRYTRADE NAMEMANUFACTURER
GermanyVirunguentAlmirall Hermal
FranceIduviranChauvin
United KingdomGerpidAstellas
ItalyIduherFarmigea
IdustatinSanofi-Aventis
JapanIMUKaken
I.D.U.Senju; Takeda
USADendridAlcon
GerpleksAllergan
StokesSmithKline & French
UkraineNoNo

Formulations

  • eye drops 0.1%;
  • eye ointment 0.25%;
  • Ointment 0.2%, 0.5%;
  • solution of 5%, 10%, 40%

Links

  • Chang, PK; Welch, AD: J. Med. Chem. (JMCMAR) 6, 428 (1963).
  • FR 1,336,866 (Roussel-Uclaf; appl. 27.7.1962).
  • GB 1024156 (Roussel-Uclaf; appl. 24.7.1963; F-prior. 27.7.1962).

References

  1. Jump up^ Prusoff, W.H. (1959) Synthesis and biological activities of iododeoxyuridine, an analog of thymidine. Biochim Biophys Acta. March; 32(1): 295–296.
  2. Jump up^ Wilhelmus KR (2010). "Antiviral treatment and other therapeutic interventions for herpes simplex virus epithelial keratitis". Cochrane Database Syst Rev 12: CD002898. doi:10.1002/14651858.CD002898.pub4PMID 21154352.
  3. Jump up to:a b c d e f Goodman and Gilman's The Pharmacological Basis of Therapeutics. Edited by Gilman AG, Rall TW, Nies AS, Taylor P. McGraw-Hill. 8th ed. 1990.
  4. Jump up^ Maxwell E. Treatment of herpes keratitis with 5-iodo-2-deoxyuridine (IDU): a clinical evaluation of 1500 cases. Am. J. Ophthalmol., 1963, 56, 571-573.
  5. Jump up^ Drugs.com: Idoxuridine ophthalmic

Further Reading

  • Seth A, Misra A, Umrigar D (2004). "Topical liposomal gel of idoxuridine for the treatment of herpes simplex: pharmaceutical and clinical implications". Pharm Dev Technol 9 (3): 277–289. doi:10.1081/PDT-200031432PMID 15458233.
  • Otto S (1998). "Radiopharmaceuticals (Strontium 89) and radiosensitizers (idoxuridine)". J Intraven Nurs 21 (6): 335–7. PMID 10392098.
  • Fauth E, Zankl H (1999). "Comparison of spontaneous and idoxuridine-induced micronuclei by chromosome painting". Mutat Res 440 (2): 147–56. doi:10.1016/s1383-5718(99)00021-2PMID 10209337.
Title: Idoxuridine
CAS Registry Number: 54-42-2
CAS Name: 2¢-Deoxy-5-iodouridine
Additional Names: 1-(2-deoxy-b-D-ribofuranosyl)-5-iodouracil; 5-iodo-2¢-deoxyuridine; IdU; IdUR; IUdR; IdUrd
Trademarks: Dendrid (Alcon); Emanil; Herpes-Gel (Master); Herplex (Allergan); Idexur; Idoxene (Spodefell); Idulea; Iduridin (Ferring); Kerecid; Ophthalmadine (SAS); Stoxil (SK & F); Virudox (Bioglan)
Molecular Formula: C9H11IN2O5
Molecular Weight: 354.10
Percent Composition: C 30.53%, H 3.13%, I 35.84%, N 7.91%, O 22.59%
Literature References: Cytotoxic nucleoside with antiviral and antineoplastic activity. Prepn: Prusoff, Biochim. Biophys. Acta 32,295 (1959); Cheong et al., J. Biol. Chem. 235, 1441 (1960); Chang, Welch, J. Med. Chem. 6, 428 (1963); Amiard, Torelli, FR1336866 (1963 to Roussel-UCLAF), C.A. 60, 3082g (1964); GB 1024156; Prystas, Sorm, Collect. Czech. Chem. Commun. 29, 121 (1964). Crystal and molecular structure: Camerman, Trotter, Acta Crystallogr. 18, 203 (1965). Review: W. H. Prusoff et al. inAntibiotics vol. 5 (pt. 2), F. E. Hahn, Ed. (Springer-Verlag, New York, 1979) pp 236-261.
Properties: Crystals from water, triclinic, dec 160° (Prusoff; Chang, Welch), 190-195° (Cheong et al.), 240° (Amiard, Torelli), over 175° (Prystas, Sorm). uv max (water): 288 nm (log e 3.87). [a]D25 +7.4° (c = 0.108 in water); [a]D20 +29° (N soda). Physical properties: Ravin, Gulesich, J. Am. Pharm. Assoc. [NS] 4, 122 (1964). pKa 8.25. pH of 0.1% aq soln, about 6. Soly at 25° in mg/ml: 2.0 in water; 2.0 in 0.2N HCl; 74.0 in 0.2N NaOH; 4.4 in methanol; 2.6 in alc; 0.014 in ether; 0.003 in chloroform; 1.6 in acetone; 1.8 in ethyl acetate; 5.7 in dioxane. LD50 i.p. in mice: 2.5 g/kg (Prusoff, 1979).
pKa: pKa 8.25
Optical Rotation: [a]D25 +7.4° (c = 0.108 in water); [a]D20 +29° (N soda)
Absorption maximum: uv max (water): 288 nm (log e 3.87)
Toxicity data: LD50 i.p. in mice: 2.5 g/kg (Prusoff, 1979)
Derivative Type: a-Anomer
Additional Names: 1-(2-Deoxy-a-D-erythro-pentofuranosyl)-5-iodouracil; 1-(2-deoxy-a-D-ribofuranosyl)-5-iodouracil; a-2¢-deoxy-5-iodouridine
Properties: Crystals from water, dec 170°. [a]D25 +21.8° (c = 0.170). uv max (water): 288 nm (log e 3.88).
Optical Rotation: [a]D25 +21.8° (c = 0.170)
Absorption maximum: uv max (water): 288 nm (log e 3.88)
Therap-Cat: Antiviral.
Keywords: Antiviral; Purines/Pyrimidinones.



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