2- and 3-Fluoro-3-deaza-1',6'-isoneplanocin: Synthesis and antiviral properties (including Ebola and Marburg).

To extend the antiviral properties of 2- and 3-fluoro-3-deazaneplanocins into the evolving 3-deaza-1',6'-isoneplanocin library, 2- (11) and 3-fluoro-1',6'-iso-3-deazaneplanocin A (12) have been explored. The requisite synthesis began with an Ullmann reaction by coupling of a protected cyclopentenyl iodide with either 2-fluoro- or 3-fluoro-3-deazaadenine. Target 12 displayed significant activity towards 5 viruses (μM): H1N1 (EC < 0.

Mechanisms of anti-vesicular stomatitis virus activity of deazaneplanocin and its 3-brominated analogs.

3-deazaneplanocin A (DzNep) and its 3-brominated analogs inhibit replication of several RNA viruses. This antiviral activity is attributed to inhibition of S-adenosyl homocysteine hydrolase (SAHase) and consequently inhibition of viral methyltransferases, impairing translation of viral transcripts. The L-enantiomers of some derivatives retain antiviral activity despite dramatically reduced inhibition of SAHase in vitro.

Enantiomeric 4'-truncated 6'-fluoro-3-deazaneplanocin and its 3-bromo derivative: Synthesis and antiviral properties, including Ebola and Marburg.

In seeking to increase the library of fluorine containing adenine-derived carbocyclic nucleoside antiviral candidates, d-like and l-like 6'-fluoro-3-deazaneplanocin and its 3-bromo derivative lacking the 4'-hydroxylmethylene substituent (2/3 and 4/5, respectively) are presented. Their synthesis was accomplished from d-ribose by developing a more facile precursor route than suggested by the literature. The 2/4d-like pair displayed significant anti-filo virial properties while the enantiomeric l-like congeners 3/5 were inactive.

5'-Nor-3-Deaza-1',6'-Isoneplanocin, the Synthesis and Antiviral Study.

The arbocyclic nucleosides aristeromycin and neplanocin have been studied as a source for new antiviral agents. A convenient synthesis of C-5'-truncated 3-deaza-1',6'-isoneplanocin, which combines the features of antiviral candidates 5'-noraristeromycin and 3-deaza-1',6'-isoneplanocin is reported from (-)-cyclopentenone to give the two C-4' epimers of 5'-nor-3-deaza isoneplanocin. Antiviral assays showed activity against the JC virus (EC = 1.

Enantiomeric 4'-Truncated 3-deaza-1',6'-isoneplanocins: Synthesis and antiviral properties including Ebola.

Enantiomeric 3-deaza-1',6'-isoneplanocins (C-3 unsubstituted 7a/7b and C-3 with a bromine 8a/8b) lacking the 4'-hydroxymethyl as mechanistically designed anti-viral targets have been prepared by utilizing the Ullmann reaction. Anti-Ebola properties were found for the D-like 7a and 8a and L-like 8b. All four products showed effects against human cytomegalovirus while D-like 7a/8a affected measles; 7a was effective versus norovirus and 8a inhibited Pichinde.

6'-Fluoro-3-deazaneplanocin: Synthesis and antiviral properties, including Ebola.

A convenient stereospecific synthesis of 6'-fluoro-3-deazaneplanocin (6) has been accomplished from d-ribose in 15 steps. It is reported to possess significant activity towards Ebola (Zaire, Vero, μM: EC < 0.36; CC 125; SI > 347) with moderate inhibition of the target enzyme (S-adenosylhomocysteine hydrolase), which did not correlate directly with its anti-Ebola effects.

5'-Hydroxy-5'-homoaristeromycin: Synthesis and antiviral properties.

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.

Both enantiomers of 6'-Isoneplanocin.

Both enantiomers of the isomer of neplanocin where the C-4' hydroxymethyl has been displaced to the 6'-position (that is, 6'-isoneplanocin) have been prepared in 5 steps from known, protected iodocyclopentenones. Both products were evaluated against a number of DNA and RNA viruses and found to be inactive. This observation is suggested to be due to the displacement of the C-4' hydroxymethyl of neplanocin (in the D-like form) away from the lysine of S-adenosylhomocysteine hydrolase, which is important for inhibition by neplanocin and, in turn, its antiviral activity.

3,7-Dideazaneplanocin: Synthesis and antiviral analysis.

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.

The Synthesis of Both Diastereomers of 5'-Methylhomoaristeromycin.

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.

Enantiomeric 3-deaza-1',6'-isoneplanocin and its 3-bromo analogue: Synthesis by the Ullmann reaction and their antiviral properties.

The 1',6'-isomer of neplanocin A possesses biological properties that have not been optimised through rationally conceived analogues. In that direction, this Letter reports the use of the Ullmann reaction to achieve enantiomeric 3-deaza-1',6'-isoneplanocin and 3-bromo-3-deaza-1',6'-isoneplanocin. These four compounds showed significant Ebola activity that is not specifically due to their inhibition of S-adenonosylhomocysteine hydrolase, as might have been expected for 3-deazaadenine carbocyclic nucleosides.

2- and 3-Fluoro-3-deazaneplanocins, 2-fluoro-3-deazaaristeromycins, and 3-methyl-3-deazaneplanocin: Synthesis and antiviral properties.

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.

Synthesis and antiviral activities of 3-deaza-3-fluoroaristeromycin and its 5' analogues.

The naturally occurring adenine based carbocyclic nucleosides aristeromycin and neplanocin A and their 3-deaza analogues have found a prominent place in the search for diverse antiviral activity agent scaffolds because of their ability to inhibit S-adenosylhomocysteine (AdoHcy) hydrolase. Following the lead of these compounds, their 3-deaza-3-fluoroaristeromycin analogues have been synthesized and their effect on S-adenosylhomocysteine hydrolase and RNA and DNA viruses determined.

The 5'-nor aristeromycin analogues of 5'-deoxy-5'-methylthioadenosine and 5'-deoxy-5'-thiophenyladenosine.

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.

The enantiomers of the 1',6'-isomer of neplanocin A: synthesis and antiviral properties.

Both enantiomers of 1',6'-isoneplanocin have been prepared from a common substituted cyclopentane epoxide in 7 steps. Both compounds were subjected to DNA and RNA viral assessments with moderate to high activity found for both towards human cytomegalovirus, measles, Ebola, norovirus, and dengue. The D-like congener also showed vaccinia and HBV effectiveness.

Assays for the identification of novel antivirals against bluetongue virus.

To identify potential antivirals against BTV, we have developed, optimized and validated three assays presented here. The CPE-based assay was the first assay developed to evaluate whether a compound showed any antiviral efficacy and have been used to screen large compound library. Meanwhile, cytotoxicity of antivirals could also be evaluated using the CPE-based assay.

Vascular leak ensues a vigorous proinflammatory cytokine response to Tacaribe arenavirus infection in AG129 mice.

Background: Tacaribe virus (TCRV) is a less biohazardous relative of the highly pathogenic clade B New World arenaviruses that cause viral hemorrhagic fever syndromes and require handling in maximum containment facilities not readily available to most researchers. AG129 type I and II interferon receptor knockout mice have been shown to be susceptible to TCRV infection, but the pathogenic mechanisms contributing to the lethal disease are unclear.

Methods: To gain insights into the pathogenesis of TCRV infection in AG129 mice, we assessed hematologic and cytokine responses during the course of infection, as well as changes in the permeability of the vascular endothelium.

6'-Methyl-5'-homoaristeromycin: a structural variation of the anti-orthopox virus candidate 5'-homoaristeromycin.

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.

C-3 halo and 3-methyl substituted 5'-nor-3-deazaaristeromycins: synthesis and antiviral properties.

To expand on the antiviral properties of 5'-noraristeromycin, synthetic entry into 3-substituted 3-deaza-5'-noraristeromyin derivatives (i.e., bromo, 4; iodo, 5; chloro, 6; and, methyl, 7) has been accomplished from a common intermediate.

Novel virostatic agents against bluetongue virus.

Bluetongue virus (BTV), a member in the family Reoviridae, is a re-emerging animal disease infecting cattle and sheep. With its recent outbreaks in Europe, there is a pressing need for efficacious antivirals. We presented here the identification and characterization of a novel virostatic molecule against BTV, an aminothiophenecarboxylic acid derivative named compound 003 (C003).

3-Bromo-3-deazaneplanocin and 3-bromo-3-deazaaristeromycin: synthesis and antiviral activity.

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.

6'-Oxa Analogs of S-Adenosylhomocysteine.

S-Adenosylmethionine (AdoMet) is a ubiquitous cofactor in biomethylations and, in that role, becomes S-adenosylhomocysteine (AdoHcy), which serves as a biofeedback inhibitor of the methylation process. In seeking to avail unexplored structural variations of AdoHcy for biological studies, its 6'-oxa analog and two corresponding carbocyclic nucleosides (based on aristeromycin and neplanocin) have been prepared via common convergent syntheses.

Development of a new tacaribe arenavirus infection model and its use to explore antiviral activity of a novel aristeromycin analog.

Background: A growing number of arenaviruses can cause a devastating viral hemorrhagic fever (VHF) syndrome. They pose a public health threat as emerging viruses and because of their potential use as bioterror agents. All of the highly pathogenic New World arenaviruses (NWA) phylogenetically segregate into clade B and require maximum biosafety containment facilities for their study.

Synthesis of the 6'-iso analogues of neplanocin A and 5'-homoneplanocin A.

An efficient synthesis of 6'-isoneplanocin A and 6-isohomoneplanocin A is reported. The key steps in the synthesis include an enyne metathesis and a regioselective oxidation.

A new synthesis and an antiviral assessment of the 4'-fluoro derivative of 4'-deoxy-5'-noraristeromycin.

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.