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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]

Both enantiomers of 1′,6′- iso neplanocin 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. In many of the other antiviral assays both compounds showed cytotoxicity making, in some cases, an EC 50 determination not possible. The S -adenosylhomocysteine hydrolase inhibitory effects showed the D-like target to be equal that of neplanocin itself and better than 3-deazaneplanocin whereas the L-like analogue was 13 to 30 times less inhibitory than 3-deazaneplanocin and neplanocin, respectively. [ABSTRACT FROM AUTHOR]

Abstract: As a surrogate for 4′-hydroxy-5′-noraristeromycin and related carbocyclic nucleosides, an efficient, enantiodivergent synthetic route to both enantiomers of 5-(6-amino-9H-purin-9-yl)-3,3-difluorocyclopentane-1,2-diol (6 and ent-6) has been developed from a common starting material ((+)-(1R,4S)-4-hydroxy-2-cyclopenten-1-yl acetate, 10). Both compounds were assayed versus a series of viruses. The only response found was for compound 6 toward vaccinia and cowpox (EC50 of 143 and 94μM, respectively) and human cytomegalovirus (EC50 of 6.2μM). Both compounds were non-cytotoxic. While not as active as cidofovir toward the orthopox viruses and ganciclovir toward cytomegalovirus, compound 6 offers a new structural prototype upon which to build for uncovering new agents effective against these viral types. [Copyright &y& Elsevier]

As a surrogate for 4′-hydroxy-5′-noraristeromycin and related carbocyclic nucleosides, an efficient, enantiodivergent synthetic route to both enantiomers of 5-(6-amino-9 H -purin-9-yl)-3,3-difluorocyclopentane-1,2-diol ( 6 and ent - 6 ) has been developed from a common starting material ((+)-(1 R ,4 S )-4-hydroxy-2-cyclopenten-1-yl acetate, 10 ). Both compounds were assayed versus a series of viruses. The only response found was for compound 6 toward vaccinia and cowpox (EC 50 of 143 and 94 μM, respectively) and human cytomegalovirus (EC 50 of 6.2 μM). Both compounds were non-cytotoxic. While not as active as cidofovir toward the orthopox viruses and ganciclovir toward cytomegalovirus, compound 6 offers a new structural prototype upon which to build for uncovering new agents effective against these viral types. [ABSTRACT FROM AUTHOR]

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 (EC50 = 1.12 µM for (4′R)-8; EC50 = 59.14 µM for (4′S)-7) and inactivity of both compounds against several DNA and RNA viruses. Both compounds lacked cytotoxicity. [ABSTRACT FROM AUTHOR]

Abstract: (−)-(1S,4R)-4-Hydroxy-2-cyclopenten-1-yl acetate provided a convenient entry point for a 16-step chiral preparation of 4′-methylaristeromycin. This procedure is adaptable to a number of carbocyclic nucleosides with a diversity of substitution at C-4′ and C-5′ and a variety of heterocyclic bases. [Copyright &y& Elsevier]

Abstract: Missing among the unsaturated carbocyclic nucleosides is the 1′,6′-double bond isomer of neplanocin A. A practical synthesis of this compound and its 2′-deoxy derivative is reported from readily accessible cyclopentenols. [Copyright &y& Elsevier]

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 lysine425of S-adenosylhomocysteine hydrolase, which is important for inhibition by neplanocin and, in turn, its antiviral activity. [ABSTRACT FROM PUBLISHER]

[Display omitted] 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 50 < 0.36, CC 50 > 357, SI > 1000), hepatitis B virus (EC 50 1.28, CC 50 > 357, SI > 279), norovirus (EC 50 0.64, CC 50 > 357, SI > 558), Ebola (EC 50 < 0.1, CC 50 > 100, SI > 1000), and Marburg (EC 50 < 0.1, CC 50 > 100, SI > 1000). On the other hand, while 11 showed limited antiviral effects, its toxicity was significant, precluding any further usefulness. [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]

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. For some members of this group, antiviral activity was also found against human cytomegalovirus, hepatitis B, norovirus, and measles. [ABSTRACT FROM AUTHOR]

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]

Enzymatic resolution of (±)-1-acetoxy-4-(nitromethyl)-2-cyclopentene (4) provides entry into a facile 10-step route to carbanucleosides and a practical 7-step procedure to 5′-nor-1′-homo carbanucleosides. These routes are illustrated for adenine derivatives but they are adaptable to any heterocyclic base. [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]

Abstract: Reductive (diisobutylaluminum hydride) ring opening of an acetal protected cyclopentenol has provided a precursor adaptable to uniquely substituted carbocyclic nucleosides. To illustrate the broad implication of this process the preparation of unnatural (+)-neplanocin F, an ara-like 2′-fluoroneplanocin, and a 6′- isomeric l-like neplanocin analog is described. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]

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. Both 7a and 8a produced SAHase inhibitory effects. However, the anti-EBOV activity of 7a and 8a cannot be readily correlated with this observation due with their contrasting IC 50 values (8a > 7a). It is to be noted that 7b showed no effects on this enzyme and 8b was minimally inhibitory. These results offer preliminary insight into the differing mechanisms of action of D- and L- like structures and enlighten structural features to guide additional antiviral agent pursuit in the isoneplanocin series. [ABSTRACT FROM AUTHOR]

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]

Abstract: 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 (IC50 of 1.2μg/mL in the neutral red assay and 14μg/mL by the visual assay) but this was accompanied by cytotoxicity in the CV-1 host cells (21–36μg/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). [Copyright &y& Elsevier]

Graphical abstract Abstract 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 50 < 0.36; CC 50 125; SI > 347) with moderate inhibition of the target enzyme (S-adenosylhomocysteine hydrolase), which did not correlate directly with its anti-Ebola effects. Compound 6 , with limited cytotoxicity, also displayed activity against measles, H1N1 and Pichinde. [ABSTRACT FROM AUTHOR]