New large-scale synthetic approach to antiretroviral agent 9-[2-(R)-(phosphonomethoxy)propyl]-2,6-diaminopurine, (R)-PMPDAP, was developed. Reaction of (R)-propanediol carbonate with 2,6-diaminopurine afforded exclusively (R)-9-(2-hydroxypropyl)-2,6-diaminopurine which was subsequently used for introduction of a phosphonomethyl residue using TsOCH(2)P(O)(OiPr)(2) or BrCH(2)P(O)(OiPr)(2) followed by deprotection of ester groups. All minor ingredients and by-products formed during the process were identified and further studied. The final product was obtained in high yield and its high enantiomeric purity (>99%) was confirmed by chiral capillary electrophoretic analysis using β-cyclodextrin as a chiral selector. Antiretroviral activity data of (R)-PMPDAP and its diverse prodrugs against HIV and FIV were investigated. Akin to (R)-PMPDAP, both prodrugs inhibit FIV replication in a selective manner. Compared to the parent molecule, the amidate prodrug was 10-fold less active against FIV in cell culture, whereas the alkoxyalkyl ester prodrug was 200-fold more potent in inhibiting FIV replication in vitro.

Institute of Organic Chemistry and Biochemistry Academy of Sciences of the Czech Republic v v i Flemingovo nám 2 16610 Prague 6 Czech Republic

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Holý A., Masojídková M. Collect. Czech. Chem. Commun. 1995;60:1196.

Holý, A.; Dvořáková, H.; De Clercq, E.; Balzarini, J. Antiretroviral enantiomeric nucleotide analogs. EP 0654037. Priority Date: August 5, 1992; Date of the Patent: May 24, 1995.

Holý A., Dvořáková H., Masojídková M. Collect. Czech. Chem. Commun. 1995;60:1390.

Arimilli M.N., Dougherty J., Cundy K.C., Bischofberger N. Antiviral Drug Res. 1999;3:69.

Arimilli M.N., Kim C.U., Dougherty J., Mulato A., Oliyai R., Shaw J.P., et al. Antivir. Chem. Chemother. 1997;8:557.

Esté J.A., Cihlar T. Antiviral Res. 2010;85:25. PubMed

Heathcote E.J., Marcellin P., Buti M., Gane E., De Man R.A., Krastev Z., Germanidis G., Lee S.S., Flisiak R., Kaita K., Manns M., et al. Gastroenterology. 2011;140:132. PubMed

Garg H., Sarin S.K., Kumar M., Garg V., Sharma C.B., Kumar A. Hepatology. 2011;53:774. PubMed

Balzarini J., Aquaro S., Perno C.-F., Witvrouw M., Holý A., De Clercq E. Biochem. Biophys. Res. Commun. 1996;219:337. PubMed

Balzarini J., Holý A., Jindrich J., Naesens L., Snoeck R., Schols D., De Clercq E. Antimicrob. Agents Chemother. 1993;37:332. PubMed PMC

HIV drug resistence early warning indicators. http://www.who.int/hiv/topics/drugresistance/hiv_dr_early_warning_indicators.pdf.

Vahlenkamp T.V., De Ronde A., Balzarini J., Naesens L., De Clercq E., van Eijk M.J., Horzinek M.C., Egberink H.F. Antimicrob. Agents Chemother. 1995;39:746. PubMed PMC

Arimilli, M.N.; Cundy, K.C.; Dougherty, J.P.; Kim, C.U.; Oliyai, R.; Stella, V.J. US Patent 5922,695, 1998.

Schultze L.M., Chapman H.H., Dubree N.J.P., Jones R.J., Kent K.M., Lee T.T., Louie M.S., Postich M.J., Prisbe E.J., Rohloff J.C., Yu R.H. Tetrahedron Lett. 1998;39:1853.

BrownRipin D.H., Teager D.S., Fortunak J., Basha S.M., Bivins N., Boddy C.N., Birn S., Catlin K.K., Houghton S.R., Jagadeesh S.T., Kumar K.A., Melton J., Muneer S., Rao L.N., Rao R.V., Ray P.C., Reddy N.G., Reddy R.M., Shekar K.C., Silverton C., Smith D.T., Stringham R.W., Subbaraju G.V., Talley F., Williams A. Org. Process Res. Dev. 2010;14:1194.

Jansa P., Holý A., Dračinský M., Baszczyňski O., Česnek M., Janeba Z. Green Chem. 2011;13:882.

Painter G.R., Almond M.R., Trost L.C., Lampert B.M., Neyts J., DeClercq E., Korba B.E., Aldern K.A., Beadle J.R., Hostetler K.Y. Antimicrob. Agents Chemother. 2007;51:3505. PubMed PMC

Jansa P., Baszczyňski O., Dračínský M., Votruba I., Zídek Z., Bahador G., Stepan G., Cihlar T., Mackman R., Holý A., Janeba Z. Eur. J. Med. Chem. 2011;46:3748. PubMed

Šolínová V., Kašička V., Sázelová P., Holý A. Electrophoresis. 2009;30:2245. PubMed

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