PURPOSE: Acyclic nucleoside phosphonates possess unique antiviral and antineoplastic activities; however, their polar phosphonate moiety is associated with low ability to cross biological membranes. We explored the potential of transdermal and topical delivery of 2,6-diaminopurine derivative cPr-PMEDAP. METHODS: In vitro diffusion of cPr-PMEDAP was investigated using formulations at different pH and concentration and with permeation enhancer through porcine and human skin. RESULTS: Ability of 0.1-5% cPr-PMEDAP to cross human skin barrier was very low with flux values ~40 ng/cm(2)/h, the majority of compound found in the stratum corneum. The highest permeation rates were found at pH 6; increased donor concentration had no influence. The permeation enhancer dodecyl 6-dimethylaminohexanoate (DDAK, 1%) increased flux of cPr-PMEDAP (up to 61 times) and its concentration in nucleated epidermis (up to ~0.5 mg of cPr-PMEDAP/g of the tissue). No deamination of cPr-PMEDAP into PMEG occurred during permeation studies, but N-dealkylation into PMEDAP mediated by skin microflora was observed. CONCLUSIONS: Transdermal or topical application of cPr-PMEDAP enabled by the permeation enhancer DDAK may provide an attractive alternative route of administration of this potent antitumor and antiviral compound.

• MeSH
• Adenine administration & dosage   MeSH
• Antiviral Agents administration & dosage   MeSH
• Administration, Cutaneous MeSH
• Dimethylamines MeSH
• Dodecanol MeSH
• Caproates metabolism   MeSH
• Hydrogen-Ion Concentration MeSH
• Skin metabolism   MeSH
• Humans MeSH
• Methylamines metabolism   MeSH
• Organophosphonates administration & dosage   MeSH
• Permeability MeSH
• Swine MeSH
• Antineoplastic Agents administration & dosage   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Adenine MeSH
• Antiviral Agents MeSH
• Dimethylamines MeSH
• dodecyl 6-(dimethylamino)hexanoate MeSH Browser
• Dodecanol MeSH
• Caproates MeSH
• Methylamines MeSH
• N(6)-cyclopropyl-9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine MeSH Browser
• Organophosphonates MeSH
• Antineoplastic Agents MeSH

2-Amino-4,6-bis[(phosphonomethoxy)alkoxy]pyrimidines bearing two equal or different achiral or chiral phosphonoalkoxy chains have been prepared either by aromatic nucleophilic substitution of 2-amino-4,6-dichloropyrimidine or by alkylation of 4,6-dihydroxy-2-(methylsulfanyl)pyrimidine with appropriate phosphonate-bearing building block. Alkylation of 4,6-dihydroxy-2-(methylsulfanyl)pyrimidine proved to be the method of choice for efficient preparation of variety of bisphosphonates. The enantiomeric purity of selected compounds was determined by capillary electrophoresis. Antiviral activity of bisphosphonates is discussed.

• MeSH
• Alkylation MeSH
• Antiviral Agents chemical synthesis   chemistry   pharmacology   MeSH
• Diphosphonates chemical synthesis   chemistry   pharmacology   MeSH
• Electrophoresis, Capillary MeSH
• HeLa Cells MeSH
• HL-60 Cells MeSH
• Humans MeSH
• Molecular Structure MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Nucleosides chemistry   MeSH
• Cell Proliferation drug effects   MeSH
• Pyrimidines chemical synthesis   chemistry   pharmacology   MeSH
• Drug Screening Assays, Antitumor MeSH
• Stereoisomerism MeSH
• Structure-Activity Relationship MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Antiviral Agents MeSH
• Diphosphonates MeSH
• Nucleosides MeSH
• Pyrimidines MeSH