We report on the synthesis of novel conformationally locked nucleoside and nucleotide derivatives, which are structurally closely related to clinically used antivirals such as didanosine and abacavir. As a suitable conformationally rigid substitute of the sugar/pseudosugar ring allowing a permanent stabilization of the nucleoside in North conformation we employed bicyclo[2.2.1]heptane (norbornane) substituted in the bridgehead position with a hydroxymethyl group and in the C-3 position with a nucleobase. Prepared nucleoside derivatives were also converted into appropriate phosphoramidate prodrugs (ProTides) in order to increase delivery of the compounds in the cells. All target compounds were evaluated in a broad antiviral and cytostatic assay panel.

• Klíčová slova
• Antiviral, Carbocyclic nucleosides, Norbornane, PI4KIIα, Purines,
• MeSH
• antivirové látky chemická syntéza   MeSH
• konformace nukleové kyseliny MeSH
• lidé MeSH
• norbornany chemická syntéza   chemie   MeSH
• nukleosidy chemická syntéza   chemie   MeSH
• nukleotidy chemická syntéza   chemie   MeSH
• stereoizomerie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antivirové látky MeSH
• norbornany MeSH
• nukleosidy MeSH
• nukleotidy MeSH

The synthesis of a novel library of purine derivatives bearing various bicyclic and polycylic substituents at the N-9 position is described. The series includes norbornanes, bicyclo[2.2.2]octanes, and bicyclo[3.2.1]octanes attached at the bridgehead position as well as bicyclo[3.1.1]heptanes, tetrahydro-1-naphthalenes, and adamantanes bonded either directly or via a linear chain to the 6-chloropurine nucleobase. A number of prepared derivatives exerted significant activity against the enterovirus. Despite attempts to correlate the activity against picornaviruses with their phosphatidylinositol 4-kinase KIIIβ inhibitory activity, it is clear that the inhibition of this host factor cannot explain the observed antiviral potency.

• Klíčová slova
• Antiviral, Coxsackievirus B3, Enteroviruses, Phosphatidylinositol 4-kinase (PI4K), Purines,
• MeSH
• antivirové látky chemická syntéza   chemie   farmakologie   toxicita   MeSH
• cytopatogenní efekt virový MeSH
• Enterovirus účinky léků   fyziologie   MeSH
• kultivované buňky MeSH
• molekulární struktura MeSH
• norbornany chemická syntéza   chemie   farmakologie   toxicita   MeSH
• přemostěné cyklické sloučeniny chemická syntéza   chemie   farmakologie   toxicita   MeSH
• puriny chemická syntéza   chemie   farmakologie   toxicita   MeSH
• replikace viru účinky léků   MeSH
• viabilita buněk účinky léků   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antivirové látky MeSH
• norbornany MeSH
• přemostěné cyklické sloučeniny MeSH
• puriny MeSH

A synthetic route toward a series of unique cyclic nucleoside phosphonates locked in South conformation is described. The desired conformation is stabilized by a substitution of the sugar moiety by bicyclo[2.2.1]heptane (norbornane) bearing a purine or pyrimidine nucleobase in the bridgehead position. Although the final phosphonate derivatives are devoid of any significant antiviral activity probably due to the unfavorable conformational properties, several intermediates and their analogs exhibit surprising activity against feline herpes virus. Since these compounds do not possess an appropriate hydroxymethyl function allowing phosphorylation and subsequent incorporation into the polynucleotide chain, it seems to be likely that these compounds act by a novel unknown mechanism of action and may represent a new possible alternative for nucleoside and nucleotide therapeutics of this widely spread feline infection. A number of derivatives exerted also a significant antiviral activity against Coxsackievirus B3 and B4.

• Klíčová slova
• Carbocyclic nucleosides, Feline herpes virus, Norbornane, Nucleoside phosphonates, Purine,
• MeSH
• antivirové látky chemická syntéza   chemie   farmakologie   MeSH
• kočičí kalicivirus účinky léků   MeSH
• lidé MeSH
• mikrobiální testy citlivosti MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• norbornany chemická syntéza   chemie   farmakologie   MeSH
• nukleotidy chemická syntéza   chemie   farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antivirové látky MeSH
• norbornany MeSH
• nukleotidy MeSH

We report on the synthesis and the study of the structure-activity relationship of novel 9-norbornyl-6-chloropurine derivatives, which exert selective antiviral activity on the replication of Coxsackievirus B3. In particular, the synthetic approaches towards norbornyl derivatives bearing diverse side chains were studied. The main goal of the study was to determine the influence of the norbornane moiety substitution at positions 5' and 6' on selective antiviral activity with special regard to the liphophilicity profile of the substituent.

• MeSH
• antivirové látky chemická syntéza   chemie   farmakologie   MeSH
• Cercopithecus aethiops MeSH
• coxsackie virózy farmakoterapie   MeSH
• enterovirus B lidský účinky léků   MeSH
• lidé MeSH
• norbornany chemická syntéza   chemie   farmakologie   MeSH
• puriny chemická syntéza   chemie   farmakologie   MeSH
• Vero buňky MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 6-chloropurine MeSH Prohlížeč
• antivirové látky MeSH
• norbornany MeSH
• puriny MeSH