Skip to main content

Advertisement

SpringerLink
Log in

Design of xanthone propionate photolabile protecting group releasing acyclovir for the treatment of ocular herpes simplex virus

  • Paper
  • Published:
Photochemical & Photobiological Sciences Aims and scope Submit manuscript

Abstract

We have attached the antiviral drug acyclovir (ACV) to a xanthone photolabile protecting group (or photocage) through the O6 position of acyclovir, a procedure designed for the treatment of ocular herpes simplex virus infections. Acyclovir is photoreleased from the photocage, under physiological conditions, with a quantum yield (ΦACV release) of 0.1–0.3 and an uncaging cross section (Φ·ε) of 450–1350 M cm-1. We demonstrate that this photorelease method outcompetes alternative reaction pathways, such as protonation. Furthermore, complete release of the drug is theoretically possible given a sufficient dose of light. Surprisingly the acyclovir photocage, also showed some antiviral activity towards HSV-1.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Notes and references

  1. G. M. Cleator and P. E. Klapper, Herpes Simplex, John Wiley & Sons, 2000.

    Google Scholar 

  2. J. S. Prepose, D. A. Leib, P. M. Stuart and D. L. Easty, Herpes simplex virus diseases: anterior segment of the eye, Mosby, St. Louis, 1996.

    Google Scholar 

  3. H. S. Toma, A. T. Murina, R. G. Areaux, D. M. Neumann, P. S. Bhattacharjee, T. P. Foster, H. E. Kaufman and J. M. Hill, Ocular HSV-1 Latency, Reactivation and Recurrent Disease, Semin. Ophthalmol., 2008, 23, 249–273.

    Article  Google Scholar 

  4. B. F. Khan, D. Pavan-Langston, Clinical Manifestations and Treatment Modalities in Herpes Simplex Virus of the Ocular Anterior Segment, Int. Ophthalmol. Clin., 2004, 44, 103–133.

    Article  Google Scholar 

  5. T. J. Liesegang, Herpes simplex virus epidemiology and ocular importance, Cornea, 2001, 20, 1–13.

    Article  CAS  Google Scholar 

  6. T. J. Liesegang, L. J. Melton, P. J. Daly and D. M. Ilstrup, Epidemiology of ocular herpes simplex. Incidence in Rochester Minn. 1950 through 1982, Arch. Ophthalmol., 1989, 107, 1155–1159.

    Article  CAS  Google Scholar 

  7. J. J. O’Brien and D. M. Campoli-Richards, Acyclovir. An updated review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy., Drugs, 1989, 37, 233–309.

    Article  Google Scholar 

  8. G. Elion, P. A. Furman, J. A. Fyfe, P. de Miranda, L. Beauchamp and H. J. Schaeffer, Selectivity of action of an antiherpetic agent, 9-(2-hydroxyethoxymethyl)guanine, Proc. Natl. Acad. Sci. U. S. A., 1977, 74, 5716–5720.

    Article  CAS  Google Scholar 

  9. H. J. Schaeffer, L. Beauchamp, P. de Miranda, G. Elion, D. J. Bauer and P. Collins, 9-(2-Hydroxyethoxymethyl)guanine Activity Against Viruses of Herpes Group, Nature, 1978, 272, 583.

    Article  CAS  Google Scholar 

  10. H. H. Balfour, Antiviral drugs, N. Engl. J. Med., 1999, 340, 1255–1268.

    Article  CAS  Google Scholar 

  11. C. Le Bourlais, L. Acar, H. Zia, P. A. Sado, T. Needham and R. Leverge, Ophthalmic drug delivery systems - Recent advances, Prog. Retinal Eye Res., 1998, 17, 33–58.

    Article  CAS  Google Scholar 

  12. M. S. Nagarsenker, V. Y. Londhe and G. D. Nadkarni, Preparation and evaluation of liposomal formulations of tropicamide for ocular delivery, Int. J. Pharm., 1999, 190, 63–71.

    Article  CAS  Google Scholar 

  13. D. Gulsen and A. Chauhan, Ophthalmic drug delivery through contact lenses, Invest. Ophthalmol. Visual Sci., 2004, 45, 2342–2347.

    Article  Google Scholar 

  14. H. J. Montgomery, B. Perdicakis, D. Fishlock, G. A. Lajoie, E. Jervis and J. G. Guillemette, Photo-Control of nitric oxide synthase activity using a caged isoform specific inhibitor, Bioorg. Med. Chem., 2002, 10, 1919–1927

    Article  CAS  Google Scholar 

  15. B. Perdicakis, H. J. Montgomery, G. L. Abbott, D. Fishlock, G. A. Lajoie, J. G. Guillemette and E. Jervis, Photocontrol of nitric oxide production in cell culture using a caged isoform selective inhibitor, Bioorg. Med. Chem., 2005, 13, 47–57

    Article  CAS  Google Scholar 

  16. K.-P. Yip, Flash photolysis of caged nitric oxide inhibits proximal tubular fluid reabsorption in free-flow nephron, Am. J. Physiol. Reg. I., 2005, 289, 620–626.

    Google Scholar 

  17. W. Liu, K. Merrett, M. Griffith, P. Fagerholm, S. Dravida, B. Heyne, J. C. Scaiano, M. A. Watsky, N. Shinozaki and N. Lagali, Recombinant human collagen for tissue engineered corneal substitutes, Biomaterials, 2008, 29, 1147.

    Article  CAS  Google Scholar 

  18. W. G. Liu, C. Deng, C. R. McLaughlin, P. Fagerholm, N. S. Lagali, B. Heyne, J. C. Scaiano, M. A. Watsky, Y. Kato, R. Munger, N. Shinozaki, F. F. Li and M. Griffith, Collagen-phosphorylcholine interpenetrating network hydrogels as corneal substitutes, Biomaterials, 2009, 30, 1551–1559.

    Article  CAS  Google Scholar 

  19. J. A. Blake, E. Gagnon, M. Lukeman and J. C. Scaiano, Photodecarboxylation of xanthone acetic acids: C-C bond heterolysis from the singlet excited state., Org. Lett., 2006, 8, 1057–1060.

    Article  CAS  Google Scholar 

  20. J. A. Blake, M. Lukeman and J. C. Scaiano, Photolabile Protecting Groups Based on the Singlet State Photodecarboxylation of Xanthone Acetic Acid, J. Am. Chem. Soc., 2009, 131, 4127–4135.

    Article  CAS  Google Scholar 

  21. G. Cosa, M. Lukeman and J. C. Scaiano, How Drug Photodegradation Studies Led to the Promise of New Therapies and Some Fundamental Carbanion Reaction Dynamics along the Way, Acc. Chem. Res., 2009, 42, 599–607.

    Article  CAS  Google Scholar 

  22. M. Lukeman and J. C. Scaiano, Carbanion-Mediated Photocages: Rapid and Efficient Photorelease with Aqueous Compatibility, J. Am. Chem. Soc., 2005, 127, 7698–7699.

    Article  CAS  Google Scholar 

  23. K. L. Harrison, N. Fairhurst, B. C. Challis, D. E. G. Shuker, Synthesis, Characterization, and Immunochemical Detection of O6-(Carboxymethyl)-2′-deoxyguanosine: A DNA Adduct Formed by Nitrosated Glycine Derivatives, Chem. Res. Toxicol., 1997, 10, 652–659.

    Article  CAS  Google Scholar 

  24. D. Pletsas, R. T. Wheelhouse, V. Pletsa, A. Nicolaou, T. C. Jenkins, M. C. Bibby and S. A. Kyrtopoulos, Polar, functionalized guanine-O6 derivatives resistant to repair by O6-alkylguanine-DNA alkyltransferase: implications for the design of DNA-modifying drugs, Eur. J. Med. Chem., 2006, 41, 330–339.

    Article  CAS  Google Scholar 

  25. S. G. Cohen, A. Parola, G. H. J. Parsons, Photoreduction by Amines, Chem. Rev., 1973, 73, 141–161

    Article  CAS  Google Scholar 

  26. D. Griller, J. A. Howard, P. R. Marriott and J. C. Scaiano, Absolute Rate Constants for the Reactions of tert-Butoxyl, tert-Butylperoxyl, and Benzophenone Triplet with amines: The Importance of a Stereoelectronic Effect, J. Am. Chem. Soc., 1981, 103, 619–623

    Article  CAS  Google Scholar 

  27. N. J. Turro, V. Ramamurthy and J. C. Scaiano, Modern Molecular Photochemistry of Organic Molecules, University Science Publishers, New York, N.Y., 2010.

    Google Scholar 

  28. H. Gao and A. K. Mitra, NMR spectral data for acyclovir prodrugs, Magn. Reson. Chem., 1999, 37.

    Google Scholar 

  29. K. O. Y. Araki-Sasaki and T. Sasabe, An SV-40 immortalized human corneal epithelial cell line and its characterization, Invest. Ophth. Vis. Sci., 1995, 36, 614–621.

    CAS  Google Scholar 

  30. P. B. P. Ngamwongsatit, W. Panbangred and A. K. Bhunia, WSt-1 based cell cytotoxicity assay as a substitute for MTT-based assay for rapid detection of toxigenic Bacillus species using CHO cell line., J. Microbiol. Methods, 2008, 73, 211–215.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Chemistry, University of Ottawa, Ottawa, Canada, K1N 6N5

    Jessie A. Blake, Liliana Jimenez & J. C. Scaiano

  2. Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, K1H 8M5, Canada

    Bettina Bareiss & May Griffith

  3. Integrative Regenerative Medicine (IGEN) Centre, Linköping University, 58185, Linköping, Sweden

    May Griffith & J. C. Scaiano

Authors
  1. Jessie A. Blake
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bettina Bareiss
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Liliana Jimenez
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. May Griffith
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J. C. Scaiano
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J. C. Scaiano.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Blake, J.A., Bareiss, B., Jimenez, L. et al. Design of xanthone propionate photolabile protecting group releasing acyclovir for the treatment of ocular herpes simplex virus. Photochem Photobiol Sci 11, 539–547 (2012). https://doi.org/10.1039/c2pp05311j

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1039/c2pp05311j

Search

Navigation