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The preparation of the C-5′ diastereomers of 5′-homoaristeromycin has been achieved in 6 steps beginning with readily available (3aR,6aR)-2,2-dimethyl-2H,3aH,4H,6aH-cyclopenta[1,3]dioxol-4-one in a Michael reaction employing chiral Evans N-acyloxazolidinones that served to direct the requisite side chain stereochemistry. The two targets were evaluated against a battery of viruses and found to possess activity only towards yellow fever. Both compounds were non-cytotoxic. [ABSTRACT FROM AUTHOR]

The preparation of two C-5'-nor-3-deazaaristeromycin diastereomeric analogues possessing a bridgehead nitrogen is described from (3aR,4R,65,6a5)-2,2-dimethyl-6-vinyltetrahydro-3aH-cyclopenta[ d][1,3]dioxol-4-ol that served as the cyclopentyl unit of the target carbocyclic nucleosides and as the scaffold upon which the compounds were built. The process evolved via a de novo approach for constructing the requisite fused imidazo unit between the aforementioned cyclopentyl ring and a readily available 2,3-dichloropyrazine. The syntheses were accomplished in 11 and 8 steps depending on the diastereomer sought. [ABSTRACT FROM AUTHOR]

To extend the potential of 5′-noraristeromycin (and its enantiomer) as potential antiviral candidates, the enantiomers of the carbocyclic 5′-nor derivatives of 5′-methylthio-5′-deoxyadenosine and 5′-phenylthio-5′-deoxyadenosine have been synthesized and evaluated. None of the compounds showed meaningful antiviral activity. [ABSTRACT FROM AUTHOR]

Abstract: The synthesis of 6′-methyl-5′-homoaristeromycin is described from a known 6′-ethyl ester. Antiviral analysis showed the (S)-6′ stereoisomer retained the vaccinia activity of the parent 5′-homoaristeromycin (1) while the (R)-6′ isomer was less active. Both were weaker than 1 towards cowpox. The diastereomers were equally active versus Epstein Barr virus while (S)-6′ was three times more active toward vesicular stomatitis virus than (R)-6′. The diastereomers were inactive towards numerous other viruses. The CC50 for both diastereomers was >300μM. [Copyright &y& Elsevier]

Abstract: The coupling reaction of 4-chloro-1H-imidazo[4,5-c]pyridine (6-chloro-3-deazapurine, 3 ) with several cyclopentyl derivatives under Mitsunubo reaction conditions provides an efficient entry into N-7 and N-9 substituted 3-deazapurine carbocyclic nucleosides of antiviral potential. The versatility of this procedure is illustrated with a new and efficient synthesis of (−)-3-deazaaristeromycin, a formal preparation of 3-deazaneplanocin A, and a route to 3-deaza-5′-homoaristeromycin. [Copyright &y& Elsevier]

Abstract: As an outgrowth of our program to explore 3-deazaadenine carbocyclic nucleosides, 3-bromo-3-deazaneplanocin (5) and 3-bromo-3-deazaaristeromycin (6) have been synthesized from a readily available cyclopentenol and cyclopentanone and either 4-amino- or 4-chloro-1H-imidazo[4,5-c]pyridine (6-amino- or 6-chloro-3-deazaadenine) in 5 steps and 7 steps, respectively. Antiviral analysis found 5 to display significant activity towards a number of (−)-ssRNA and a few dsDNA viruses. Compound 6 was less active than 5 against selected examples of those viruses affected by 5. [Copyright &y& Elsevier]

The 3-deaza analogs of the naturally occurring adenine-based carbocyclic nucleosides aristeromycin and neplanocin possess biological properties that have not been optimized. In that direction, this paper reports the strategic placement of a fluorine atom at the C-2 and C-3 positions and a methyl at the C-3 site of the 3-deazaadenine ring of the aforementioned compounds. The synthesis and S -adenosylhomocysteine hydrolase inhibitory and antiviral properties of these targets are described. Some, but not all, compounds in this series showed significant activity toward herpes, arena, bunya, flavi, and orthomyxoviruses. [ABSTRACT FROM AUTHOR]

Synthetically combining the C-4′ side-chain structural features of the antiviral candidates 5′-methylaristeromycin and 5′-homoaristeromycin into a diastereomeric pair of C-4′ side-chain dihydroxylated aristeromycins ( 6 and 7 ) is reported. Broad antiviral analyses of the both targets found promising effects towards HBV ( 6 , 6.7 μM and 7 , 7.74 μM) and HCMV (only 7 , 0.72 μM). No other activity was found. Neither of the diastereomers was cytotoxic in the assays performed. [ABSTRACT FROM AUTHOR]

Abstract: The carbocyclic nucleoside 3-deazaaristeromycin has shown biological promise but a library of its derivatives upon which to expand this property is lacking. To address this situation, the synthesis of the two diastereomers of 2′-fluoro-3-deazaaristeromycin is described in a multistep convergent process that calls upon d-ribose for construction of the cyclopentyl fluoro units. [Copyright &y& Elsevier]