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

• Type of Material: Article
• Authors: Amarender Manchoju, Institut de Recherches Cliniques de Montréal; Renaud Zelli, Institut de Recherches Cliniques de Montréal; Gang Wang, Institut de Recherches Cliniques de Montréal; Carla Eymard, Institut de Recherches Cliniques de Montréal; Adrian Oo, Emory University; Mona Nemer, University of Ottawa; Michel Prevost, Institut de Recherches Cliniques de Montréal; Baek Kim, Emory University; Yvan Guindon, Institut de Recherches Cliniques de Montréal
• Language: English
• Date: 2022-01-01
• Publisher: MDPI
• Publication Version: Final Published Version
• Copyright Statement: © 2022 by the authors.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3390/molecules27020564
• Title of Journal or Parent Work: MOLECULES
• Volume: 27
• Issue: 2
• Grant/Funding Information: This research was supported by Natural Sciences and Engineering Research Council (NSERC), Canadian Glycomics Network (Glyconet) and CIHR to Yvan Guindon and Mona Nemer.
• Keywords: Physical Sciences; ADDITIONS; Chemistry; Chemistry, Multidisciplinary; epoxidation; triphosphorylation; glycosylation; RdRp; SARS-CoV-2; Life Sciences & Biomedicine; Science & Technology; NUCLEOSIDE; Biochemistry & Molecular Biology; quaternary stereocenter; DISCOVERY; nucleoside analogues; EPOXIDATION; COVID-19
• Research Categories: Health Sciences, Immunology; Chemistry, Organic; Chemistry, Biochemistry; Biology, Microbiology

Abstract

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 enan-tioselective 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.