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Ronald T. Borchardt - One of the best experts on this subject based on the ideXlab platform.
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synthesis of homologated halovinyl derivatives from Aristeromycin and their inhibition of human placental s adenosyl l homocysteine hydrolase
Nucleosides Nucleotides & Nucleic Acids, 1998Co-Authors: Stanislaw F Wnuk, Ronald T. Borchardt, Chongsheng Yuan, Morris J RobinsAbstract:Abstract Moffatt oxidation of 2′,3′-O-isopropylideneAristeromycin (1a) and treatment of the 5′-carboxaldehyde with [(p-tolylsulfonyl)methylene]triphenylphosphorane gave the homologated vinylsulfone 2. Treatment of 2 with tributylstannane/AIBN gave the (E/Z)-vinylstannanes which were converted into the E and Z fluoro- and iodovinyl analogs. Chain extension via the 5′-cyano-5′-deoxy derivative 10a gave the 6′-carboxaldehyde of homoAristeromycin. S-Adenosyl-L-homocysteine hydrolase was strongly inhibited by the fluorovinyl, 5b, and iodovinyl, 4b and 7b, compounds, and time-dependent kinetics were observed [1–2 μM (Ki) and 0.1–0.2 min−1 (k inact)]. The mechanism of inactivation was shown to involve addition of water at the vinyl 5′ or 6′ carbons with elimination of halide. This paper is dedicated to the late Professor T. Hata.
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Aristeromycin 5 carboxaldehyde a potent inhibitor of s adenosyl l homocysteine hydrolase
Journal of Medicinal Chemistry, 1996Co-Authors: Siming Liu, Chongsheng Yuan, Ronald T. BorchardtAbstract:In an earlier study, Liu et al. (Bioorg. Med. Chem. Lett. 1992, 2, 1741−1744) showed that both the E and Z isomers of 4‘,5‘-didehydro-5‘-fluoroAristeromycin were very potent irreversible inhibitors...
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1 r 2 s 3 r 9 2 3 dihydroxycyclopentan 1 yl adenine and 3 deaza adenine analogues of Aristeromycin which exhibit potent antiviral activity with reduced cytotoxicity
Antiviral Chemistry & Chemotherapy, 1993Co-Authors: M Hasobe, David R Borcherding, Michael S. Wolfe, H Liang, D B Aultriche, Ronald T. BorchardtAbstract:Two synthetic analogues of Aristeromycin, which were shown in a separate study to be inhibitors of S-adenosylhomocysteine hydrolase and devoid of substrate activity with adenosine kinase and adenosine deaminase, were found in this study to inhibit vaccinia virus replication in murine L929 cells and to have reduced cytotoxicity compared with that of the parent compound. Aristeromycin was shown to produce cytocidal effects on murine L929 cells, whereas the synthetic analogues produced cytostatic effects on cell growth. The antiviral effects of these synthetic analogues are correlated with their ability to elevate the intracellular ratio of S-adenosylhomocysteine/S-adenosylmethionine. These results confirm that S-adenosylhomocysteine hydrolase is the molecular target which mediates the antiviral effects of Aristeromycin and that transformation of Aristeromycin by cellular adenosine kinase mediates its cytocidal properties.
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effects of 4 modified analogs of Aristeromycin on the metabolism of s adenosyl l homocysteine in murine l929 cells
Molecular Pharmacology, 1993Co-Authors: D B Aultriche, David R Borcherding, Michael S. Wolfe, M Hasobe, Younha Lee, Chongsheng Yuan, Ronald T. BorchardtAbstract:(1'R,2'S,3')-9-(2',3'-Dihydroxycyclopentan-1'-yl)adenine (DHCaA), (1'R,2'S,3'R)-9-(2',3'-dihydroxycyclopentan-1'-yl)-3-deazaadenine (3-deaza-DHCaA), (4'R)-4'-methyl-DHCaA, and (4'R)-4'-vinyl-DHCaA, which are analogs of the carbocyclic nucleoside Aristeromycin, were synthesized earlier by our laboratory and were shown to be potent inhibitors of purified bovine liver S-adenosylhomocysteine (AdoHcy) hydrolase (EC 3.3.1.1). In the present study, these analogs were shown to produce rapid (within 15 min) and concentration-dependent (0.03-10 microM) inhibition of AdoHcy hydrolase in cultured murine L929 cells [relative order of inhibitory activity, DHCaA = 3-deaza-DHCaA >> (4'R)-4'-vinyl-DHCaA = (4'R)-4'-methyl-DHCaA]. The relative potencies of these inhibitors on the L929 AdoHcy hydrolase were consistent with their inhibitory effects on the recombinant forms of rat liver and human placental enzymes. This inhibition of L929 cellular AdoHcy hydrolase persisted for up to 48 hr. The inhibition of the L929 AdoHcy hydrolase resulted in a significant increase in the cellular concentrations of AdoHcy, whereas the cellular S-adenosylmethionine (AdoMet) levels remained relatively constant, thereby elevating the AdoHcy/AdoMet ratios. Maximum increases in AdoHcy levels and AdoHcy/AdoMet ratios occurred within 6 hr of exposure to the inhibitors and persisted for at least 24 hr. At a concentration of 1 microM, DHCaA and 3-deaza-DHCaA increased AdoHcy/AdoMet ratios to approximately 0.8 (after 24 hr of exposure to the inhibitors), whereas (4'R)-4'-vinyl-DHCaA and (4'R)-4'-methyl-DHCaA elevated AdoHcy/AdoMet ratios to approximately 0.15, compared with control levels of 0.05. Treatment of L929 cells with concentrations of DHCaA, 3-deaza-DHCaA, (4'R)-4'-vinyl-DHCaA, and (4'R)-4'-methyl-DHCaA up to 10 microM did not result in changes in cellular levels of endogenous nucleotides (e.g., CTP, UTP, ATP, and GTP). In contrast, cells treated with 10 microM Aristeromycin for 6 hr contained reduced cellular levels of CTP, ATP, and GTP and significant levels of Aristeromycin triphosphate and a GTP metabolite of this carbocyclic nucleoside. These data clearly show that the 4'-modified analogs [DHCaA, 3-deaza-DHCaA, (4'R)-4'-vinyl-DHCaA, and (4'R)-4'-methyl-DHCaA] retain inhibitory activity toward cellular AdoHcy hydrolase, causing elevated levels of AdoHcy and elevated AdoHcy/AdoMet ratios. However, these analogs are devoid of substrate or inhibitory activity toward cellular adenosine kinase. In addition, Aristeromycin is rapidly metabolized in murine L929 cell lysates, i.e., > 60% of the Aristeromycin had been metabolized in 6 hr. In contrast, neither DHCaA nor 3-deaza-DHCaA showed any decrease in concentration after incubation with cell lysates for up to 6 hr.
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short communication 1 r 2 5 3 r 9 2 3 dihydroxycyclopentan 1 yl ade nine and 3 deaza adenine analogues of Aristeromycin which exhibit potent antiviral activity with reduced cytotoxicity
1993Co-Authors: M Hasobe, Michael S. Wolfe, H Liang, D B Aultriche, Ronald T. BorchardtAbstract:Summary Two synthetic analogues of aristef.omycin, which were i:.! shown in a separate study to be inhibitors of S-adeno- . sylhomocysteine hydrolase and devoid of substrate activity with adenosine kinase and adenosine deami nase, were found in this study to inhibit vaccinia Virus replication in murine L929 cells and to have reduced cytotoxicity compared with that of the parent compound. Aristeromycin was shown to produce cytocidal effects on murine L929 cells, whereas the synthetic analogues produced cytostatic effects on cell growth. The antiviral effects of these synthetic analogues are correlated with their ability to elevate the intracellular ratio of S-adenosylhomocysteinel S-adenosylmethionine. These results confirm that S-adenosylhomocysteine hydrolase is the molecular target which mediates the antiviral effects of aristero mycin and that transformation of aristerornycin by cellular adenosine kinase mediates its cytocidal properties.
Stewart W Schneller - One of the best experts on this subject based on the ideXlab platform.
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preparation of 8 aza 7 deazaAristeromycin and neplanocin a and their 5 homologs
Journal of Heterocyclic Chemistry, 2015Co-Authors: Haisheng Wang, Yan Zhang, Wei Ye, Stewart W SchnellerAbstract:The synthesis of new members of the Aristeromycin and neplaoncin A families of carbocyclic nucleosides possessing the 1H-pyrazolo[3,4-d]pyrimidine ring is reported. For this purpose, an adapted route to 4-amino-1H-pyrazolo[3,4-d]pyrimidine is described.
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The 5'-nor Aristeromycin analogues of 5'-deoxy-5'-methylthioadenosine and 5'-deoxy-5'-thiophenyladenosine.
Nucleosides Nucleotides & Nucleic Acids, 2014Co-Authors: Stewart W SchnellerAbstract: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.
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Development of a New Tacaribe Arenavirus Infection Model and Its Use to Explore Antiviral Activity of a Novel Aristeromycin Analog
2013Co-Authors: Brian B. Gowen, Eric J Sefing, Donald F Smee, Min-hui Wong, Deanna Larson, Kie-hoon Jung, John D. Morrey, Stewart W SchnellerAbstract: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-a/b and-c receptor-deficient mice. Titration of the virus by intraperitoneal (i.p.) challenge of AG129 mice resulted in an LD 50 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 mM, 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 finding
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development of a new tacaribe arenavirus infection model and its use to explore antiviral activity of a novel Aristeromycin analog
PLOS ONE, 2010Co-Authors: Brian B. Gowen, Eric J Sefing, Donald F Smee, Min-hui Wong, Deanna Larson, Kie-hoon Jung, John D. Morrey, Ramona Skirpstunas, Stewart W SchnellerAbstract: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.
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Development of a new tacaribe arenavirus infection model and its use to explore antiviral activity of a novel Aristeromycin analog.
Public Library of Science (PLoS), 2010Co-Authors: Brian B. Gowen, Eric J Sefing, Donald F Smee, Min-hui Wong, Deanna Larson, Kie-hoon Jung, John D. Morrey, Ramona Skirpstunas, Stewart W SchnellerAbstract: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.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 LD(50) 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
Jiseong Yoon - One of the best experts on this subject based on the ideXlab platform.
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design synthesis and anti rna virus activity of 6 fluorinated Aristeromycin analogues
Journal of Medicinal Chemistry, 2019Co-Authors: Jiseong Yoon, Dnyandev B Jarhad, Young Sup Shin, Hea Ok Kim, Gyudong Kim, Hongrae Kim, Pramod K Sahu, Hyuk Woo Lee, Su Bin WangAbstract:The 6'-fluorinated Aristeromycins were designed as dual-target antiviral compounds aimed at inhibiting both the viral RNA-dependent RNA polymerase (RdRp) and the host cell S-adenosyl-l-homocysteine (SAH) hydrolase, which would indirectly target capping of viral RNA. The introduction of a fluorine at the 6'-position enhanced the inhibition of SAH hydrolase and the activity against RNA viruses. The adenosine and N6-methyladenosine analogues 2a-e showed potent inhibition against SAH hydrolase, while only the adenosine derivatives 2a-c exhibited potent antiviral activity against all tested RNA viruses such as Middle East respiratory syndrome-coronavirus (MERS-CoV), severe acute respiratory syndrome-coronavirus, chikungunya virus, and/or Zika virus. 6',6'-DifluoroAristeromycin (2c) showed the strongest antiviral effect for MERS-CoV, with a ∼2.5 log reduction in infectious progeny titer in viral load reduction assay. The phosphoramidate prodrug 3a also demonstrated potent broad-spectrum antiviral activity, possibly by inhibiting the viral RdRp. This study shows that 6'-fluorinated Aristeromycins can serve as starting points for the development of broad-spectrum antiviral agents that target RNA viruses.
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design synthesis and anti rna virus activity of 6 fluorinated Aristeromycin analogues
Journal of Medicinal Chemistry, 2019Co-Authors: Jiseong Yoon, Dnyandev B Jarhad, Young Sup Shin, Shuhao Qu, Pramod K Sahu, Su Bin Wang, Yun Jeong Kong, Tongshin ChangAbstract:The 6′-fluorinated Aristeromycins were designed as dual-target antiviral compounds aimed at inhibiting both the viral RNA-dependent RNA polymerase (RdRp) and the host cell S-adenosyl-l-homocysteine (SAH) hydrolase, which would indirectly target capping of viral RNA. The introduction of a fluorine at the 6′-position enhanced the inhibition of SAH hydrolase and the activity against RNA viruses. The adenosine and N6-methyladenosine analogues 2a–e showed potent inhibition against SAH hydrolase, while only the adenosine derivatives 2a–c exhibited potent antiviral activity against all tested RNA viruses such as Middle East respiratory syndrome-coronavirus (MERS-CoV), severe acute respiratory syndrome-coronavirus, chikungunya virus, and/or Zika virus. 6′,6′-DifluoroAristeromycin (2c) showed the strongest antiviral effect for MERS-CoV, with a ∼2.5 log reduction in infectious progeny titer in viral load reduction assay. The phosphoramidate prodrug 3a also demonstrated potent broad-spectrum antiviral activity, poss...
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Asymmetric Synthesis of (-)-6'-β-Fluoro-Aristeromycin via Stereoselective Electrophilic Fluorination.
Organic Letters, 2017Co-Authors: Jiseong Yoon, Dnyandev B Jarhad, Young Sup Shin, Mahesh S. Majik, Varughese A. Mulamoottil, Shuhao Qu, Jiyong Park, Mu-hyun BaikAbstract:(−)-6′-β-Fluoro-Aristeromycin (2), a potent inhibitor of S-adenosylhomocysteine (AdoHcy) hydrolase, has been synthesized via stereoselective electrophilic fluorination followed by a purine base build-up approach. Interestingly, purine base condensation using a cyclic sulfate resulted in a synthesis of (+)-5′-β-fluoro-isoAristeromycin (2a). Computational analysis indicates that the fluorine atom controlled the regioselectivity of the purine base substitution.
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Asymmetric Synthesis of (−)-6′-β-Fluoro-Aristeromycin via Stereoselective Electrophilic Fluorination
2017Co-Authors: Gyudong Kim, Dnyandev B Jarhad, Jiseong Yoon, Mahesh S. Majik, Varughese A. Mulamoottil, Jiyong Park, Young Sup Shin, Xiyan Hou, Mu-hyun BaikAbstract:(−)-6′-β-Fluoro-Aristeromycin (2), a potent inhibitor of S-adenosylhomocysteine (AdoHcy) hydrolase, has been synthesized via stereoselective electrophilic fluorination followed by a purine base build-up approach. Interestingly, purine base condensation using a cyclic sulfate resulted in a synthesis of (+)-5′-β-fluoro-isoAristeromycin (2a). Computational analysis indicates that the fluorine atom controlled the regioselectivity of the purine base substitution
Tongshin Chang - One of the best experts on this subject based on the ideXlab platform.
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design synthesis and anti rna virus activity of 6 fluorinated Aristeromycin analogues
Journal of Medicinal Chemistry, 2019Co-Authors: Jiseong Yoon, Dnyandev B Jarhad, Young Sup Shin, Shuhao Qu, Pramod K Sahu, Su Bin Wang, Yun Jeong Kong, Tongshin ChangAbstract:The 6′-fluorinated Aristeromycins were designed as dual-target antiviral compounds aimed at inhibiting both the viral RNA-dependent RNA polymerase (RdRp) and the host cell S-adenosyl-l-homocysteine (SAH) hydrolase, which would indirectly target capping of viral RNA. The introduction of a fluorine at the 6′-position enhanced the inhibition of SAH hydrolase and the activity against RNA viruses. The adenosine and N6-methyladenosine analogues 2a–e showed potent inhibition against SAH hydrolase, while only the adenosine derivatives 2a–c exhibited potent antiviral activity against all tested RNA viruses such as Middle East respiratory syndrome-coronavirus (MERS-CoV), severe acute respiratory syndrome-coronavirus, chikungunya virus, and/or Zika virus. 6′,6′-DifluoroAristeromycin (2c) showed the strongest antiviral effect for MERS-CoV, with a ∼2.5 log reduction in infectious progeny titer in viral load reduction assay. The phosphoramidate prodrug 3a also demonstrated potent broad-spectrum antiviral activity, poss...
Dnyandev B Jarhad - One of the best experts on this subject based on the ideXlab platform.
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6 6 difluoro Aristeromycin is a potent inhibitor of mers coronavirus replication
bioRxiv, 2021Co-Authors: Jessika C Zevenhovendobbe, Dnyandev B Jarhad, Lak Shin Jeong, S K Tripathi, H W Lee, Eric J Snijder, Clara C PosthumaAbstract:The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has highlighted the lack of treatments to combat infections with human or (potentially) zoonotic CoVs. Thus, it is critical to develop and evaluate antiviral compounds that either directly target CoV functions or modulate host functions involved in viral replication. Here, we demonstrate that low-micromolar concentrations of 6,6-difluoro-Aristeromycin (DFA), an adenosine nucleoside analogue, strongly inhibit the replication of Middle East respiratory syndrome coronavirus (MERS-CoV) in a cell-based infection assay. DFA was designed to target S-adenosylhomocysteine (SAH) hydrolase and, consequently, may affect intracellular levels of the methyl donor S-adenosylmethionine, which is used by two CoV methyltransferases involved in the capping of the 5 end of the viral mRNAs. Passaging of wild-type MERS-CoV in the presence of DFA selected a mutant with a ~100-fold decreased DFA sensitivity. This drug-resistant population carried various amino acid substitutions in the viral nonstructural proteins (nsp), including mutations in nsp16, which has 2-O-methyltransferase activity, and nsp13, which contains a nucleoside triphosphate hydrolase activity that has also been implicated in CoV capping. Based on our results, we hypothesize that DFA directly or indirectly affects viral cap methylation, either by inhibiting the viral enzymes involved or by binding to SAH hydrolase. We also evaluated the antiviral activity of DFA against other betacoronaviruses, but found it to have limited impact on their replication, while being quite cytotoxic to the Calu-3 cells used for this comparison. Nevertheless, our results justify the further characterization of DFA derivatives as an inhibitor of MERS-CoV replication.
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design synthesis and anti rna virus activity of 6 fluorinated Aristeromycin analogues
Journal of Medicinal Chemistry, 2019Co-Authors: Jiseong Yoon, Dnyandev B Jarhad, Young Sup Shin, Hea Ok Kim, Gyudong Kim, Hongrae Kim, Pramod K Sahu, Hyuk Woo Lee, Su Bin WangAbstract:The 6'-fluorinated Aristeromycins were designed as dual-target antiviral compounds aimed at inhibiting both the viral RNA-dependent RNA polymerase (RdRp) and the host cell S-adenosyl-l-homocysteine (SAH) hydrolase, which would indirectly target capping of viral RNA. The introduction of a fluorine at the 6'-position enhanced the inhibition of SAH hydrolase and the activity against RNA viruses. The adenosine and N6-methyladenosine analogues 2a-e showed potent inhibition against SAH hydrolase, while only the adenosine derivatives 2a-c exhibited potent antiviral activity against all tested RNA viruses such as Middle East respiratory syndrome-coronavirus (MERS-CoV), severe acute respiratory syndrome-coronavirus, chikungunya virus, and/or Zika virus. 6',6'-DifluoroAristeromycin (2c) showed the strongest antiviral effect for MERS-CoV, with a ∼2.5 log reduction in infectious progeny titer in viral load reduction assay. The phosphoramidate prodrug 3a also demonstrated potent broad-spectrum antiviral activity, possibly by inhibiting the viral RdRp. This study shows that 6'-fluorinated Aristeromycins can serve as starting points for the development of broad-spectrum antiviral agents that target RNA viruses.
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design synthesis and anti rna virus activity of 6 fluorinated Aristeromycin analogues
Journal of Medicinal Chemistry, 2019Co-Authors: Jiseong Yoon, Dnyandev B Jarhad, Young Sup Shin, Shuhao Qu, Pramod K Sahu, Su Bin Wang, Yun Jeong Kong, Tongshin ChangAbstract:The 6′-fluorinated Aristeromycins were designed as dual-target antiviral compounds aimed at inhibiting both the viral RNA-dependent RNA polymerase (RdRp) and the host cell S-adenosyl-l-homocysteine (SAH) hydrolase, which would indirectly target capping of viral RNA. The introduction of a fluorine at the 6′-position enhanced the inhibition of SAH hydrolase and the activity against RNA viruses. The adenosine and N6-methyladenosine analogues 2a–e showed potent inhibition against SAH hydrolase, while only the adenosine derivatives 2a–c exhibited potent antiviral activity against all tested RNA viruses such as Middle East respiratory syndrome-coronavirus (MERS-CoV), severe acute respiratory syndrome-coronavirus, chikungunya virus, and/or Zika virus. 6′,6′-DifluoroAristeromycin (2c) showed the strongest antiviral effect for MERS-CoV, with a ∼2.5 log reduction in infectious progeny titer in viral load reduction assay. The phosphoramidate prodrug 3a also demonstrated potent broad-spectrum antiviral activity, poss...
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Asymmetric Synthesis of (-)-6'-β-Fluoro-Aristeromycin via Stereoselective Electrophilic Fluorination.
Organic Letters, 2017Co-Authors: Jiseong Yoon, Dnyandev B Jarhad, Young Sup Shin, Mahesh S. Majik, Varughese A. Mulamoottil, Shuhao Qu, Jiyong Park, Mu-hyun BaikAbstract:(−)-6′-β-Fluoro-Aristeromycin (2), a potent inhibitor of S-adenosylhomocysteine (AdoHcy) hydrolase, has been synthesized via stereoselective electrophilic fluorination followed by a purine base build-up approach. Interestingly, purine base condensation using a cyclic sulfate resulted in a synthesis of (+)-5′-β-fluoro-isoAristeromycin (2a). Computational analysis indicates that the fluorine atom controlled the regioselectivity of the purine base substitution.
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Asymmetric Synthesis of (−)-6′-β-Fluoro-Aristeromycin via Stereoselective Electrophilic Fluorination
2017Co-Authors: Gyudong Kim, Dnyandev B Jarhad, Jiseong Yoon, Mahesh S. Majik, Varughese A. Mulamoottil, Jiyong Park, Young Sup Shin, Xiyan Hou, Mu-hyun BaikAbstract:(−)-6′-β-Fluoro-Aristeromycin (2), a potent inhibitor of S-adenosylhomocysteine (AdoHcy) hydrolase, has been synthesized via stereoselective electrophilic fluorination followed by a purine base build-up approach. Interestingly, purine base condensation using a cyclic sulfate resulted in a synthesis of (+)-5′-β-fluoro-isoAristeromycin (2a). Computational analysis indicates that the fluorine atom controlled the regioselectivity of the purine base substitution