The lack of antiviral activity of recently described (S)-3-(adenin-9-yl)-2-(phosphonomethoxy)propanoic acid, or (S)-CPMEA in brief, has been speculated to possibly be due to the increased hydrophilicity of the molecule and, thus, by its limited cellular permeability. Efficient syntheses of novel lipophilic prodrugs of (S)-CPMEA masking either the carboxylic group or preferably both the phosphonate and carboxylic moieties, have been developed in order to increase bioavailability of the parent compound. Two prodrugs of (S)-CPMEA, namely phosphonate bis-amidate 15 and phenyloxy amidate 16, exhibited pan-genotypic anti-HCV activity at submicromolar concentrations.

• MeSH
• adenin analogy a deriváty   chemická syntéza   chemie   farmakologie   MeSH
• antivirové látky chemická syntéza   chemie   farmakologie   MeSH
• Hepacivirus účinky léků   MeSH
• mikrobiální testy citlivosti MeSH
• molekulární struktura MeSH
• organofosfonáty chemická syntéza   chemie   farmakologie   MeSH
• prekurzory léčiv chemická syntéza   chemie   farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

We prepared a novel series of conformationally restricted bicyclonucleosides and nucleotides. The synthetic approach employed a ring closing metathesis to provide access to both 6 and 7 membered saturated and unsaturated rings linking the 3' to 5' methylene groups of the sugar. The bicyclonucleosides were also transformed to the corresponding phosphoramidate prodrugs by an innovative one-pot protocol of boronate ester protection, coupling of the phosphoryl chloridate and deprotection of the boronate. A similar strategy was also employed for the synthesis of the corresponding monophosphates as crucial intermediates for the synthesis of selected triphosphates. The biological properties of the nucleosides and monophosphate prodrugs were assessed for antiviral and cytostatic activities in cell based assays whilst the triphosphates were evaluated in enzymatic assays. The lack of significant effects suggests that the linkage of the 3' to 5'via a ring system and the subsequent conformational restriction of the ribose ring to the South conformation are incompatible with the kinases and polymerases that recognize nucleosides and their metabolites.

• MeSH
• adenin chemie   MeSH
• antivirové látky chemická syntéza   metabolismus   farmakologie   MeSH
• Hepacivirus účinky léků   MeSH
• konformace sacharidů MeSH
• lidé MeSH
• molekulární modely MeSH
• nádorové buněčné linie MeSH
• nukleotidy chemická syntéza   metabolismus   farmakologie   MeSH
• prekurzory léčiv metabolismus   MeSH
• racionální návrh léčiv MeSH
• techniky syntetické chemie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH