Nucleotide Analogues Bearing a C2′ or C3′-Stereogenic All-Carbon Quaternary Center as SARS-CoV-2 RdRp Inhibitors

The design of novel nucleoside triphosphate (NTP) analogues bearing an all-carbon quaternary center at C2′ or C3′ is described. The construction of this all-carbon stereogenic center involves the use of an intramoleculer photoredox-catalyzed reaction. The nucleoside analogues (NA) hydroxyl functiona...

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Published in:Molecules (Basel, Switzerland) Vol. 27; no. 2; p. 564
Main Authors: Manchoju, Amarender, Zelli, Renaud, Wang, Gang, Eymard, Carla, Oo, Adrian, Nemer, Mona, Prévost, Michel, Kim, Baek, Guindon, Yvan
Format: Journal Article
Language:English
Published: Switzerland MDPI AG 17.01.2022
MDPI
Subjects:
Alcohol
Antiviral Agents - chemical synthesis
Antiviral Agents - chemistry
Antiviral Agents - pharmacology
Carbon
Carbon - chemistry
Coronaviruses
COVID-19
Enzymes
epoxidation
Heterocyclic Compounds, 4 or More Rings - chemical synthesis
Heterocyclic Compounds, 4 or More Rings - chemistry
Heterocyclic Compounds, 4 or More Rings - pharmacology
Laboratories
nucleoside analogues
Nucleotides - chemical synthesis
Nucleotides - chemistry
Nucleotides - pharmacology
Phosphorylation
quaternary stereocenter
RdRp
RNA polymerase
RNA-Dependent RNA Polymerase - antagonists & inhibitors
SARS-CoV-2
SARS-CoV-2 - drug effects
SARS-CoV-2 - enzymology
Severe acute respiratory syndrome coronavirus 2
Stereoisomerism
Viruses
COVID-19
SARS-CoV-2
epoxidation
RdRp
nucleoside analogues
quaternary stereocenter
glycosylation
triphosphorylation
ISSN:1420-3049, 1420-3049
Online Access:Get full text
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Summary:The design of novel nucleoside triphosphate (NTP) analogues bearing an all-carbon quaternary center at C2′ or C3′ is described. The construction of this all-carbon stereogenic center involves the use of an intramoleculer photoredox-catalyzed reaction. The nucleoside analogues (NA) hydroxyl functional group at C2′ was generated by diastereoselective epoxidation. In addition, highly enantioselective and diastereoselective Mukaiyama aldol reactions, diastereoselective N-glycosylations and regioselective triphosphorylation reactions were employed to synthesize the novel NTPs. Two of these compounds are inhibitors of the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2, the causal virus of COVID-19.
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This paper is dedicated to Professor Stephen Hanessian-a mentor, colleague and friend.
ISSN:1420-3049
1420-3049
DOI:10.3390/molecules27020564