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Start Over Author "Feng, Joy" Journal bioorganic medicinal chemistry letters
8 results on '"Feng, Joy"'

1. Discovery of a 2'-fluoro-2'-C-methyl C-nucleotide HCV polymerase inhibitor and a phosphoramidate prodrug with favorable properties.

Author

Kirschberg TA, Metobo S, Clarke MO, Aktoudianakis V, Babusis D, Barauskas O, Birkus G, Butler T, Byun D, Chin G, Doerffler E, Edwards TE, Fenaux M, Lee R, Lew W, Mish MR, Murakami E, Park Y, Squires NH, Tirunagari N, Wang T, Whitcomb M, Xu J, Yang H, Ye H, Zhang L, Appleby TC, Feng JY, Ray AS, Cho A, and Kim CU

Subjects
Amides chemistry, Amides pharmacokinetics, Amides pharmacology, Animals, Antiviral Agents pharmacokinetics, Caco-2 Cells, Cell Line, Cricetinae, Drug Discovery, Drug Resistance, Viral, Halogenation, Hepacivirus genetics, Hepacivirus physiology, Hepatitis C drug therapy, Humans, Methylation, Molecular Docking Simulation, Nucleosides pharmacokinetics, Phosphoric Acids chemistry, Phosphoric Acids pharmacokinetics, Phosphoric Acids pharmacology, Point Mutation, Prodrugs chemistry, Prodrugs pharmacokinetics, Prodrugs pharmacology, Viral Nonstructural Proteins genetics, Viral Nonstructural Proteins metabolism, Virus Replication drug effects, Antiviral Agents chemistry, Antiviral Agents pharmacology, Hepacivirus drug effects, Nucleosides chemistry, Nucleosides pharmacology, Viral Nonstructural Proteins antagonists & inhibitors
Abstract

A series of 2'-fluorinated C-nucleosides were prepared and tested for anti-HCV activity. Among them, the triphosphate of 2'-fluoro-2'-C-methyl adenosine C-nucleoside (15) was a potent and selective inhibitor of the NS5B polymerase and maintained activity against the S282T resistance mutant. A number of phosphoramidate prodrugs were then prepared and evaluated leading to the identification of the 1-aminocyclobutane-1-carboxylic acid isopropyl ester variant (53) with favorable pharmacokinetic properties including efficient liver delivery in animals., (Copyright © 2017. Published by Elsevier Ltd.)

Published
2017
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2. Discovery of β-D-2'-deoxy-2'-α-fluoro-4'-α-cyano-5-aza-7,9-dideaza adenosine as a potent nucleoside inhibitor of respiratory syncytial virus with excellent selectivity over mitochondrial RNA and DNA polymerases.

Author

Clarke MO, Mackman R, Byun D, Hui H, Barauskas O, Birkus G, Chun BK, Doerffler E, Feng J, Karki K, Lee G, Perron M, Siegel D, Swaminathan S, and Lee W

Subjects
Adenosine chemical synthesis, Adenosine pharmacology, Antiviral Agents chemical synthesis, Antiviral Agents pharmacology, Aza Compounds chemistry, DNA-Directed DNA Polymerase metabolism, Drug Evaluation, Preclinical, Nucleic Acid Synthesis Inhibitors chemical synthesis, Nucleic Acid Synthesis Inhibitors pharmacology, RNA metabolism, RNA, Mitochondrial, RNA-Dependent RNA Polymerase metabolism, Respiratory Syncytial Viruses drug effects, Structure-Activity Relationship, Virus Replication drug effects, Adenosine chemistry, Antiviral Agents chemistry, DNA-Directed DNA Polymerase chemistry, Nucleic Acid Synthesis Inhibitors chemistry, RNA chemistry, RNA-Dependent RNA Polymerase antagonists & inhibitors, Respiratory Syncytial Viruses enzymology, Respiratory Syncytial Viruses physiology
Abstract

Novel 4'-substituted β-d-2'-deoxy-2'-α-fluoro (2'd2'F) nucleoside inhibitors of respiratory syncytial virus (RSV) are reported. The introduction of 4'-substitution onto 2'd2'F nucleoside analogs resulted in compounds demonstrating potent cell based RSV inhibition, improved inhibition of the RSV polymerase by the nucleoside triphosphate metabolites, and enhanced selectivity over incorporation by mitochondrial RNA and DNA polymerases. Selectivity over the mitochondrial polymerases was found to be extremely sensitive to the specific 4'-substitution and not readily predictable. Combining the most potent and selective 4'-groups from N-nucleoside analogs onto a 2'd2'F C-nucleoside analog resulted in the identification of β-D-2'-deoxy-2'-α-fluoro-4'-α-cyano-5-aza-7,9-dideaza adenosine as a promising nucleoside lead for RSV., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Published
2015
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3. Synthesis and characterization of 1'-C-cyano-2'-fluoro-2'-C-methyl pyrimidine nucleosides as HCV polymerase inhibitors.

Author

Kirschberg TA, Mish MR, Zhang L, Squires NH, Wang KY, Cho A, Feng JY, Fenaux M, Babusis D, Park Y, Ray AS, and Kim CU

Subjects
Amides chemistry, Amides pharmacology, Cell Line, Halogenation, Hepacivirus enzymology, Hepatitis C drug therapy, Hepatitis C virology, Humans, Methylation, Phosphoric Acids chemistry, Phosphoric Acids pharmacology, Prodrugs chemistry, Prodrugs pharmacology, RNA-Dependent RNA Polymerase antagonists & inhibitors, Replicon drug effects, Antiviral Agents chemistry, Antiviral Agents pharmacology, Hepacivirus drug effects, Pyrimidine Nucleosides chemistry, Pyrimidine Nucleosides pharmacology
Abstract

The first synthesis of 1'-C-CN, 2'-F, 2'-C-Me pyrimidines is described. Anti-HCV activity was assessed and compared to the 1'-C-CN, 2'-C-Me as well as the 2'-F, 2'-C-Me pyrimidines. A phosphoramidate prodrug of the cytidine derivative showed activity in the low micromolar range against HCV replicons., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Published
2015
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4. Preparation and biological evaluation of 1'-cyano-2'-C-methyl pyrimidine nucleosides as HCV NS5B polymerase inhibitors.

Author

Mish MR, Cho A, Kirschberg T, Xu J, Zonte CS, Fenaux M, Park Y, Babusis D, Feng JY, Ray AS, and Kim CU

Subjects
Antiviral Agents chemical synthesis, Antiviral Agents chemistry, Dose-Response Relationship, Drug, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, Microbial Sensitivity Tests, Molecular Conformation, Nucleosides chemical synthesis, Nucleosides chemistry, Pyrimidine Nucleosides chemical synthesis, Pyrimidine Nucleosides chemistry, RNA-Dependent RNA Polymerase metabolism, Structure-Activity Relationship, Viral Nonstructural Proteins metabolism, Antiviral Agents pharmacology, Enzyme Inhibitors pharmacology, Hepacivirus drug effects, Hepacivirus enzymology, Nucleosides pharmacology, Pyrimidine Nucleosides pharmacology, RNA-Dependent RNA Polymerase antagonists & inhibitors, Viral Nonstructural Proteins antagonists & inhibitors
Abstract

The first synthesis of 1'-cyano-2'-C-methyl pyrimidine nucleosides is described. Anti-HCV activity of these nucleosides and their nucleotide phosphoramidate prodrugs was assessed and compared to the 1'-unsubstituted counterparts and to the related 1'-cyano-2'-C-methyl C-nucleoside parent of GS-6620., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Published
2014
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5. Evaluation of 2'-α-fluorine modified nucleoside phosphonates as potential inhibitors of HCV polymerase.

Author

Parrish JP, Lee SK, Boojamra CG, Hui H, Babusis D, Brown B, Shih IH, Feng JY, Ray AS, and Mackman RL

Subjects
Antiviral Agents chemical synthesis, Antiviral Agents pharmacology, Cell Line, DNA-Directed RNA Polymerases metabolism, Drug Evaluation, Preclinical, Humans, Organophosphonates chemical synthesis, Organophosphonates pharmacology, Virus Replication drug effects, Antiviral Agents chemistry, DNA-Directed RNA Polymerases antagonists & inhibitors, Fluorine chemistry, Hepacivirus enzymology, Organophosphonates chemistry, Ribonucleosides chemistry
Abstract

Ribonucleoside phosphonate analogues containing 2'-α-fluoro modifications were synthesized and their potency evaluated against HCV RNA polymerase. The diphosphophosphonate (triphosphate equivalent) adenine and cytidine analogues displayed potent inhibition of the HCV polymerase in the range of 1.9-2.1 μM, but only modest cell-based activity in the HCV replicon. Pro-drugs of the parent nucleoside phosphonates improved the cell-based activity., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Published
2013
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6. Bifunctional inhibition of HIV-1 reverse transcriptase: a first step in designing a bifunctional triphosphate.

Author

Piao D, Basavapathruni A, Iyidogan P, Dai G, Hinz W, Ray AS, Murakami E, Feng JY, You F, Dutschman GE, Austin DJ, Parker KA, and Anderson KS

Subjects
Binding Sites, Drug Design, HIV Infections drug therapy, HIV Reverse Transcriptase chemistry, Humans, Models, Molecular, Nucleosides chemistry, Nucleosides pharmacology, Polyethylene Glycols chemistry, Reverse Transcriptase Inhibitors metabolism, HIV Reverse Transcriptase antagonists & inhibitors, HIV-1 enzymology, Reverse Transcriptase Inhibitors chemistry, Reverse Transcriptase Inhibitors pharmacology
Abstract

The onset of resistance to approved anti-AIDS drugs by HIV necessitates the search for novel inhibitors of HIV-1 reverse transcriptase (RT). Developing single molecular agents concurrently occupying the nucleoside and nonnucleoside binding sites in RT is an intriguing idea but the proof of concept has so far been elusive. As a first step, we describe molecular modeling to guide focused chemical syntheses of conjugates having nucleoside (d4T) and nonnucleoside (TIBO) moieties tethered by a flexible polyethylene glycol (PEG) linker. A triphosphate of d4T-6PEG-TIBO conjugate was successfully synthesized that is recognized as a substrate by HIV-1 RT and incorporated into a double-stranded DNA., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Published
2013
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7. Synthesis and characterization of 2'-C-Me branched C-nucleosides as HCV polymerase inhibitors.

Author

Cho A, Zhang L, Xu J, Babusis D, Butler T, Lee R, Saunders OL, Wang T, Parrish J, Perry J, Feng JY, Ray AS, and Kim CU

Subjects
Administration, Oral, Animals, Antiviral Agents pharmacokinetics, Antiviral Agents pharmacology, Aza Compounds pharmacokinetics, Aza Compounds pharmacology, Cell Line, Cricetinae, Dogs, Hepacivirus enzymology, Hepacivirus growth & development, Hepatocytes drug effects, Hepatocytes virology, Humans, Injections, Intravenous, Primary Cell Culture, Purine Nucleosides pharmacokinetics, Purine Nucleosides pharmacology, Pyrimidine Nucleosides pharmacokinetics, Pyrimidine Nucleosides pharmacology, RNA-Dependent RNA Polymerase metabolism, Rats, Viral Nonstructural Proteins metabolism, Antiviral Agents chemical synthesis, Aza Compounds chemical synthesis, Hepacivirus drug effects, Purine Nucleosides chemical synthesis, Pyrimidine Nucleosides chemical synthesis, RNA-Dependent RNA Polymerase antagonists & inhibitors, Viral Nonstructural Proteins antagonists & inhibitors
Abstract

A series of 2'-C-methyl branched purine and pyrimidine C-nucleosides were prepared. Their anti-HCV activity and pharmacological properties were profiled, and compared with known 2'-C-Me N-nucleoside counterparts. In particular, 2'-C-Me 4-aza-7,9-dideazaadenosine C-nucleoside (2) was found to have potent and selective anti-HCV activity in vitro as well as a favorable pharmacokinetic profile and in vivo potential for enhanced potency over the corresponding N-nucleoside., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Published
2012
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8. Synthesis and antiviral activity of a series of 1'-substituted 4-aza-7,9-dideazaadenosine C-nucleosides.

Author

Cho A, Saunders OL, Butler T, Zhang L, Xu J, Vela JE, Feng JY, Ray AS, and Kim CU

Subjects
Adenosine chemical synthesis, Adenosine chemistry, Adenosine pharmacology, Antiviral Agents chemistry, Aza Compounds chemical synthesis, Aza Compounds chemistry, Aza Compounds pharmacology, Humans, Molecular Structure, Nucleosides chemistry, Viral Nonstructural Proteins antagonists & inhibitors, Viral Nonstructural Proteins drug effects, Antiviral Agents chemical synthesis, Antiviral Agents pharmacology, Hepacivirus drug effects, Nucleosides chemical synthesis, Nucleosides pharmacology
Abstract

A series of 1'-substituted analogs of 4-aza-7,9-dideazaadenosine C-nucleoside were prepared and evaluated for the potential as antiviral agents. These compounds showed a broad range of inhibitory activity against various RNA viruses. In particular, the whole cell potency against HCV when R=CN was attributed to inhibition of HCV NS5B polymerase and intracellular concentration of the corresponding nucleoside triphosphate., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Published
2012
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