ABSTRACT
Objective To synthesize 3,7-dideazaneplanocin and evaluate its antiviral potential. Methods The target 3,7-dideazaneplanocin has been prepared in five steps from a readily available cyclopentenol. A thorough in vitro antiviral analysis was conducted versus both DNA and RNA viruses. Results A rational synthesis of 3,7-dideazaneplanocin was conceived and successfully pursued in such a way that it can be adapted to various analogs of 3,7-dideazaneplanocin. Using standard antiviral assays, no activity for 3,7-dideazaneplanocn was found. Conclusion Two structural features are necessary for adenine-based carbocyclic nucleosides (like neplanocin) for potential antiviral properties: (i) inhibition of S-adenosylhomocysteine hydrolase and/or (ii) C-5' activation via the mono-nucleotide. These two requisite adenine structural features to fit these criteria are not present in in the target 3,7-dideazaneplanocin: (i) an N-7 is necessary for inhibition of the hydrolase and the N-3 is claimed to be essential for phosphorylation at C-5'. Thus, it is not surprising that 3,7-dideazaneplaoncin lacked antiviral properties.
Subject(s)
Antiviral Agents/pharmacology , DNA Viruses/drug effects , Enzyme Inhibitors/pharmacology , Pyridones/pharmacology , RNA Viruses/drug effects , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Hydrolases/antagonists & inhibitors , Hydrolases/metabolism , Microbial Sensitivity Tests , Molecular Conformation , Pyridones/chemical synthesis , Pyridones/chemistryABSTRACT
A synthetic route to (1S,2S,3R,5S)-3-(6-amino-9H-purin-9-yl)-5-fluorocyclopentane-1,2-diol (that is, the 4'-fluoro derivative of 4'-deoxy-5'-noraristeromycin, 3) is described via a fluorinated cyclopentanol, which is in contrast to existing schemes where fluorination occurred once the purine ring was present. Compound 3 was assayed versus a number of viruses. A favorable response was observed towards measles (IC(50) of 1.2 microg/mL in the neutral red assay and 14 microg/mL by the visual assay) but this was accompanied by cytotoxicity in the CV-1 host cells (21-36 microg/mL). Among the viruses unaffected by 3 were human cytomegalovirus and the poxviruses (vaccinia and cowpox), which are three viruses that were inhibited by the 4',4'-difluoro analog of 3 (that is, 2).
Subject(s)
Adenosine/analogs & derivatives , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Cytomegalovirus/drug effects , Poxviridae/drug effects , Adenosine/chemical synthesis , Adenosine/chemistry , Adenosine/pharmacology , Antiviral Agents/chemical synthesis , Cell Line , Cytomegalovirus/growth & development , Humans , Hydrocarbons, Fluorinated/chemical synthesis , Hydrocarbons, Fluorinated/chemistry , Hydrocarbons, Fluorinated/pharmacology , Inhibitory Concentration 50 , Magnetic Resonance Spectroscopy , Poxviridae/growth & development , Stereoisomerism , Structure-Activity RelationshipABSTRACT
5'-Fluoro-5'-deoxyaristeromycin (2) has been prepared via a Mitsunobu coupling of (1S,2S,3R,4S)-2,3-(cyclopentylidenedioxy)-4-fluoromethylcyclopentan-1-ol with N6-bis-boc protected adenine. This procedure is adaptable to preparing a number of 5'-fluoro-5'-deoxycarbocyclic nucleoside analogs with diversity in the heterocyclic base. Antiviral analysis found promising activity for 2 toward measles but no other viruses. No cytotoxicity was observed for 2.
Subject(s)
Deoxyadenosines/chemical synthesis , Adenosine/analogs & derivatives , Adenosine/chemical synthesis , Adenosine/pharmacology , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Cell Line , Chlorocebus aethiops , Deoxyadenosines/pharmacology , HeLa Cells , Humans , Hydrocarbons, Fluorinated/chemical synthesis , Hydrocarbons, Fluorinated/pharmacology , Vero CellsABSTRACT
(3aS,4S,6R,6aR)-Tetrahydro-2,2-dimethyl-6-vinyl-3aH-cyclopenta[d][1,3]-dioxol-4-ol, itself available from ribose, provided a convenient entry point for an 18-step preparation of carbocyclic sinefungin. This procedure is adaptable to a number of carbocyclic sinefungin analogs with diversity of heterocyclic base and in the amino acid bearing side chain.
ABSTRACT
(+/-)-1-Deazaaristeromycin (4) has been reported to be an inactivator of S-adenosylhomocysteine (AdoHcy) hydrolase and, as a consequence, to affect S-adenosylmethionine (AdoMet) mediated macromolecular biomethylations. To extend this to our program focused on 5'-noraristeromycin derivatives as inhibitors of the same hydrolase enzyme as potential antiviral agents, both enantiomers of 1-deaza-5'-noraristeromycin (5 and 20) have been prepared. Compounds 5 and 20 were evaluated against the following viruses: vaccinia, cowpox, monkeypox, Ebola, herpes simplex type 1 and 2, human cytomegalovirus, Epstein Barr, varicella zoster, hepatitis B, hepatitis C, HIV-1 and HIV-2, adenovirus type 1, measles, Pichinde, parainfluenza type 3, influenza A (H1N1 and H3N2), influenza B, Venezuelan equine encephalitis, rhinovirus type 2, respiratory syncytial, yellow fever, and West Nile. No activity was found nor was there any cytotoxicity to the viral host cells.
