Search

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]

Abstract: The potent antiviral potential of 5′-amino-5′-deoxy-5′-noraristeromycin (2) is limited by associated toxicity. To seek derivatives of 2 that circumvent this undesirable property, three amino substituted derivatives (acetyl, 3; formyl, 4; and methyl, 5) of 2 have been prepared in 4–7 steps from the same intermediate, (1S,4R)-4-(6-chloropurin-9-yl)cyclopent-2-en-1-ol (6). Key steps involved an improved Pd(0)-catalyzed allylic azidation and a novel Pd(0)-catalyzed allylic amidation. The three target compounds were evaluated against a large number of viruses and found to be inactive except for a very weak effect of 5 on human cytomegalovirus, varicella zoster virus, and Epstein–Barr virus. There was also no noteworthy cytotoxicity associated with the new derivatives. Thus, these results indicate variation of the cyclopentyl amine of 2 does not offer a means to improve upon its antiviral potential. [Copyright &y& Elsevier]

Prior to this work only two examples of carbanucleosides possessing a C-1′/C-6′ double bond had been reported and they were minor derivatized side products arising during other targeted syntheses. To develop this structural feature into a new class of potential antiviral agents, the 5′-nor derivative of aristeromycin with such an olefinic structure (6) represents the first example. In this regard, treatment of (1′S,2′S,3′S,4′R,5′S)-6-chloro-9-(2′,3′-isopropylidenedioxy-6′-oxabicyclo[3.1.0]hex-4′-yl)purine (7) with sodium methoxide yielded 6 via an E′2-like elimination pathway. A convenient way to the C-4′ epimer of 6 (that is, 17) also arose during these studies and is described. Antiviral analysis of 6 and 17 failed to produce any significant activity. [Copyright &y& Elsevier]

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: 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 promising antiviral properties of 3′-fluoro-3′-deoxyadenosine and 4′,4′-difluoro-4′-deoxy-5′-noraristeromycin prompted the synthesis of the corresponding 3′-fluoro derivatives of 5′-noraristeromycin. These target compounds, which were prepared from the same readily accessible cyclopentenol, were found to be inactive when subjected to 31 viral assays. The results have some implications on the mechanism of antiviral action of 5′-noraristeromycin and provide guidance for future geminal-difluoro analog design. [Copyright &y& Elsevier]

[Display omitted] 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 / 4 d -like pair displayed significant anti-filo virial properties while the enantiomeric l -like congeners 3 / 5 were inactive. Target compounds 2 / 4 also were active towards measles and norovirus. The effect of 2 / 4 is further evidence of the role fluoro-derived adenine carbocyclic nucleoside can play in antiviral drug discovery. Furthermore, the simplicity of their synthesis lends them to more efficacious analogs and to scale-up optimization. There were no other relevant antiviral properties for 2 / 3 and 4 / 5 (except BK polyomavirus for 3 / 5). [ABSTRACT FROM AUTHOR]

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: Adenine is a poor substrate for the Mitsunobu process to carbocyclic nucleosides. However, N-6 amino bis-Boc-protected adenine is reported herein to undergo an efficient coupling under these conditions as a result of its increased solubility and the reduced competing nucleophilicity of the free adenine amino substituent. Products from this reaction are readily converted to aristeromycin, neplanocin, and analogs there from, including 5′-homoaristeromycin, a promising antiviral agent. [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: 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. An extensive antiviral analysis showed 7 to be basically inactive (except for weak effects against VSV) and there were no general trends among the halo compounds (except versus reovirus-1 and influenza B). Individually, compound 4 was most favorable towards HCMV, VZV, HBV, and VV; product 5 against HBV, VSV, VV, influenza B, HCMV, and measles; and, target 6 towards Punta Toro, VSV, measles, parainflucenza-3, influenza A (H5N1), and influenza B. The methyl target 7 was inactive in all viral assays. [Copyright &y& Elsevier]

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). The virostatic efficacy of C003 could be improved via chemical modification, leading to a de novo synthesized compound 052 (C052). The 50% effective concentrations (EC50) of C003 and C052 were determined at 1.7660±73 µM and 0.2760.12 µM, respectively. The 50% cytotoxicity concentration (CC50) of C003 was over 100 µM and the CC50 of C052 was at 82.69 µM. Accordingly, the 50% selective index (SI50) of C003 and C052 against BTV was over 57 and 306, respectively. The inhibitory effect of C003/C052 on BTV-induced apoptosis was also confirmed via the inhibition of caspase-3/-7 activation post BTV infection. C003/C052 could inhibit BTV induced CPE even when added as late as 24 h.p.i., indicating that they might act at late stage of viral life-cycle. C003/C052 could reduce over two-logs of both the progeny virus production and the number of genomic viral RNA copies. Interestingly, both the activation of host autophagy and viral protein expression were inhibited post BTV infection when cells were treated with C003 and C052, suggesting that C003/C052 might act as virostatic agents via inhibiting host autophagy activation. Although further investigations might be needed to pin down the exact mechanism of C003/C052, our finding suggested that these compounds might be potent lead compounds with potential novel mechanism of action against BTV. [ABSTRACT FROM AUTHOR]

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. Tacaribe virus (TCRV) is a nonpathogenic member of clade B that is closely related to the VHF arenaviruses at the amino acid level. Despite this relatedness, TCRV lacks the ability to antagonize the host interferon (IFN) response, which likely contributes to its inability to cause disease in animals other than newborn mice. Methodology/Principal Findings: Here we describe a new mouse model based on TCRV challenge of AG129 IFN-α/β and -γ receptor-deficient mice. Titration of the virus by intraperitoneal (i.p.) challenge of AG129 mice resulted in an LD50 of ∼100 fifty percent cell culture infectious doses. Virus replication was evident in the serum, liver, lung, spleen, and brain 4-8 days after inoculation. MY-24, an aristeromycin derivative active against TCRV in cell culture at 0.9 μM, administered i.p. once daily for 7 days, offered highly significant (P<0.001) protection against mortality in the AG129 mouse TCRV infection model, without appreciably reducing viral burden. In contrast, in a hamster model of arenaviral hemorrhagic fever based on challenge with clade A Pichinde arenavirus, MY-24 did not offer significant protection against mortality. Conclusions/Significance: MY-24 is believed to act as an inhibitor of S-adenosyl-L-homocysteine hydrolase, but our findings suggest that it may ameliorate disease by blunting the effects of the host response that play a role in disease pathogenesis. The new AG129 mouse TCRV infection model provides a safe and cost-effective means to conduct early-stage pre-clinical evaluations of candidate antiviral therapies that target clade B arenaviruses. [ABSTRACT FROM AUTHOR]

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]

Abstract: Formycin is a naturally occurring biologically responsive C-nucleoside. In pursuing the design and syntheses of novel C-nucleosides, convenient access to carbocyclic C-nucleosides based on the formycin framework was a goal. One such target was carbocyclic 4′-epi-formycin (4). This compound is reported via a procedure based on an asymmetric aldol/ring closure metathesis strategy. To provide a preliminary glimpse into the biological characterization of 4 an antiviral assay was conducted. Target 4 was found to be inactive and to lack cytotoxicity to the host cells. [Copyright &y& Elsevier]

Abstract: Formycin is a naturally occurring C-glycoside (C-nucleoside) that possesses antitumor, antibacterial, antifungal, and antiviral activity. In connection with our ongoing interest in the design and syntheses of C-nucleoside derived antiviral agents this report describes the preparation of carbocyclic formycin and its 7-hydroxy (oxo) analog lacking the C-4′ hydroxylmethylene moiety in racemic form (4 and 6, respectively). An antiviral analysis of (±)-4 did not disclose any activity. [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]