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fbtwitterlinkedinvimeoflicker grey 14rssslideshare1
Publisher: Wiley-Blackwell
Languages: English
Types: Part of book or chapter of book
Subjects: RM
The use of pronucleotides to circumvent the well-known drawbacks of nucleotide analogs has played a significant role in the area of antiviral and anticancer drug delivery. Several motifs have been designed to mask the negative charges on the phosphorus moiety of either nucleoside monophosphates or nucleoside phosphonates, in order to increase their hydrophobicity and allow entry of the compound into the cell. Among them the bis-amidate analogs, having two identical amino acids as masking groups through a P–N bond, represent a more recent approach for the delivery of nucleotide analogs, endowed with antiviral or anticancer activity. Different synthetic strategies are commonly used for preparing phosphorodiamidates of nucleosides. In this protocol, we would like to focus on the description of the synthetic methodology that in our hand gave the best results using 2′-3′-didehydro-2′-3′-dideoxythymidine (d4T, Stavudine) as model nucleoside. A second strategy for preparing diamidates of nucleoside phosphonates will be reported using {[2-(6-amino-9 H-purin-9-yl)ethoxy]methyl}phosphonic acid (PMEA, adefovir) as model substrate.
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    • Ariza, M. E. 2005. Current Prodrug Strategies for the Delivery of Nucleotides into Cells. Drug Design Reviews - Online 2: 273-387.
    • Derudas, M., Carta, D., Brancale, A., Vanpouille, C., Lisco, A., Margolis, L., Balzarini, J., McGuigan, C. 2009. The application of phosphoramidate protide technology to acyclovir confers anti-HIV inhibition. J. Med. Chem. 52: 5520-30.
    • He, G.-X., Krise, J. P., Oliyai, R. 2007. Prodrugs of Phosphonates, Phosphinates, and Phosphates. Springer 223-264: New York.
    • Hecker, S. J., Erion, M. D. 2008. Prodrugs of phosphates and phosphonates. J. Med. Chem. 51: 2328-45.
    • Jansa, P., Baszczyňski, O., Dračínský, M., Votruba, I., Zídek, Z., Bahador, G., Stepan, G., Cihlar, T., Mackman, R., Holý, A., Janeba, Z. 2011. A novel and efficient onepot synthesis of symmetrical diamide (bis-amidate) prodrugs of acyclic nucleoside phosphonates and evaluation of their biological activities. Eur. J. Med. Chem. 46: 3748-54
    • Keith, K. A., Hitchcock, M. J., Lee, W. A., Holy, A., Kern, E. R. . 2003. Evaluation of nucleoside phosphonates and their analogs and prodrugs for inhibition of orthopoxvirus replication. Antimicrob. Agents Chemother. 47: 2193-2198.
    • Krise, J. P., Stella, V. J. 1996. Prodrugs of phosphates, phosphonates, and phosphinates. Adv.Drug Deliver. Rev. 19: 287-310.
    • Li, F., Maag, H., Alfredson, T. 2007. Prodrugs of nucleoside analogues for improved oral absorption and tissue targeting. J. Pharm. Sci. 97: 1109-1134.
    • McGuigan, C., Bourdin, C., Derudas, M., Hamon, N., Hinsinger, K., Kandil, S., Madela, K., Meneghesso, S., Pertusati, F., Serpi, M., Slusarczyk, M., Chamberlain, S., Kolykhalov, A., Vernachio, J., Vanpouille, C., Introini, A., Margolis, L., Balzarini, J. 2013. Design, synthesis and biological evaluation of phosphorodiamidate prodrugs of antiviral and anticancer nucleosides. Eur. J. Med. Chem. 70: 326-340.
    • McGuigan, C., Derudas, M., Gonczy, B., Hinsinger, K., Kandil, S., Pertusati, F., Serpi, M., Snoeck, R., Andrei, G., Balzarini, J., McHugh, T. D.; Maitra, A., Akorli, E., Evangelopoulos, D., Bhakta, S. 2014. ProTides of N-(3-(5-(2′-deoxyuridine))prop2-ynyl)octanamide as potential anti-tubercular and anti-viral agents. Bioorg. Med. Chem. 22: 2816-2824.
    • McGuigan, C., Gilles, A., Madela, K., Aljarah, M., Holl, S., Jones, S., Vernachio, J. H. J. Ames B., Bryant, K. D. 2010. Phosphoramidate ProTides of 2'-C-methylguanosine as highly potent inhibitors of Hepatitis C Virus. Study of their in vitro and in vivo properties. J. Med. Chem. 53: 4949-4957.
    • McGuigan, C., Madela, K., Aljarah, M., Bourdin, C., M., A., Barrett, E., Jones, S., Kolykhalov, A., Bleiman, K., Bryant, K. D., Ganguly, B., Gorovits, E., Henson, G., Hunley, D., Hutchins, J., Muhammad, J., Obikhod, A., Patti, J., Walters, C. R., Wang, J., Vernachio, J., Ramamurty, V. S. C., Battina, S. K.; S., C. 2011. Phosphorodiamidates as a Promising New Phosphate Prodrug Motif for Antiviral Drug Discovery: Application to Anti-HCV Agents. J. Med. Chem. 54: 8632-8645.
    • McGuigan, C., Murziani, P., Slusarczyk, M., Gonczy, B., Vande Voorde, J., Liekens, S., Balzarini, J. 2011. Phosphoramidate ProTides of the anticancer agent FUDR successfully deliver the preformed bioactive monophosphate in cells and confer advantage over the parent nucleoside. J. Med. Chem. 54: 7247-58.
    • McGuigan, C., Pathirana, R. N., Balzarini, J., De Clercq, E. 1993. Intracellular delivery of bioactive AZT nucleotides by aryl phosphate derivatives of AZT. J. Med. Chem. 36: 1048-1.
    • Mehellou, Y., Balzarini, J., McGuigan, C. 2009. Aryloxy Phosphoramidate triester: a technology for delivering monophosphorylated nucleosides and sugars into cells. ChemMedChem, 4: 1779-91.
    • Pertusati, F., Hinsinger, K., Flynn, Á. S., Powell, N., Tristram, A., Balzarini, J., McGuigan, C. 2014. PMPA and PMEA prodrugs for the treatment of HIV infections and human papillomavirus (HPV) associated neoplasia and cancer. Eur. J. Med. Chem. 78, 259-268.
    • Pertusati, F., Serpi, M., McGuigan, C. 2012. Medicinal chemistry of nucleoside phosphonate prodrugs for antiviral therapy. Antiviral Chem. Chemoth., 22: 181- 203.
    • Peterson, L. W., McKenna, C. E. 2009. Prodrug approaches to improving the oral absorption of antiviral nucleotide analogues. Exp. Opinion on Drug Deliv. 6: 405- 420.
    • Reiser, H., Wang, J., Chong, L., Watkins, W. J., Ray, A. S., Shibata, R., Birkus, G., Cihlar, T., Wu, S., Li, B., Liu, X., Henne, I. N., Wolfgang, G. H. I., Desai, M., Rhodes, G. R., Fridland, A., Lee, W. A., Plunkett, W., Vail, D.; Thamm, D. H., Jeraj, R.; Tumas, D. B. 2008. GS-9219-A Novel Acyclic Nucleotide Analogue with Potent Antineoplastic Activity in Dogs with Spontaneous Non-Hodgkin's Lymphoma. Clin. Cancer Res. 14: 2824-2832.
    • Schultz, C. 2003. Prodrugs of biologically active phosphate esters. Bioorg. Med. Chem., 11: 885-898.
    • Serpi, M., Bibbo, R., Rat, S., Roberts, H., Hughes, C., Caterson, B., Alcaraz, M. J., Gibert, A. T., Verson, C. R., McGuigan, C. 2012. Novel phosphoramidate prodrugs of N-acetyl-(D)-glucosamine with antidegenerative activity on bovine and human cartilage explants. J. Med. Chem. 55: 4629-39.
    • Serpi, M., Madela, K., Pertusati, F., Slusarczyk, M. 2013. Synthesis of phosphoramidate prodrugs: ProTide approach. Curr. Protoc. Nucleic Acid Chem. 53: 15.5.1-15.5.15.
    • Slusarczyk, M., Lopez, M. H., Balzarini, J., Mason, M., Jiang, W. G., Blagden, S., Thompson, E.; Ghazaly, E., McGuigan, C. 2014. Application of ProTide Technology to Gemcitabine: A Successful Approach to Overcome the Key Cancer Resistance Mechanisms Leads to a New Agent (NUC-1031) in Clinical Development. J. Med. Chem. 57, 1531-1542.
    • Starrett, J. E. Jr., Tortolani, D. R., Russell, J., Hitchcock, M. J. M., Whiterock, V., Martin, J. C., Mansuri, M. M. 1994. Synthesis, Oral Bioavailability Determination, and in vitro Evaluation of Prodrugs of the Antiviral Agent 9-[2- (Phosphonomethoxy)ethyl]adenine (PMEA). J. Med. Chem. 37: 1857-1864.
    • Toti, K. S., Derudas, M., Pertusati, F., Sinnaeve, D., Van den Broeck, F., Margamuljana, L., Martins, J. C., Herdewijn, P., Balzarini, J., McGuigan, C., Van Calenbergh, S. 2014. Synthesis of an Apionucleoside Family and Discovery of a Prodrug with Anti-HIV Activity. J. Org. Chem., 79: 5097-5112.
    • Wagner, C. R., Iyer, V. V., McIntee, E. J. 2000. Pronucleotides: Toward the in vivo delivery of antiviral and anticancer nucleotides. Med. Res. Rev. 20: 417-451.
    • Wolfgang, G. H. I., Shibata, R., Wang, J., Ray, A. S., Wu, S., Doerrfler, E., Reiser, H., Lee, W. A., Birkus, G., Christensen, N. D., Andrei, G., Snoeck, R. 2009. GS-9191, a Novel Topical Prodrug of the Nucleotide Analog PMEG (9-(2- Phosphonylmethoxyethyl) guanine), with Anti-proliferative Activity and Possible Utility in the Treatment of HPV Lesions. Antimicrob. Agents Chemother. 53: 2777-2784.
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