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Synthesis and Biological Evaluation of Phosphoester and Phosphorothioate Prodrugs of STING Agonist 3′,3′-c-Di(2′F,2′dAMP)

  • Markéta Pimková Polidarová
    Markéta Pimková Polidarová
    Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo Náměstí 2, Prague 160 00, Czech Republic
    Faculty of Science, Charles University, Albertov 6, Prague 128 00, Czech Republic
  • Petra Břehová
    Petra Břehová
    Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo Náměstí 2, Prague 160 00, Czech Republic
  • Martin Maxmilian Kaiser
    Martin Maxmilian Kaiser
    Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo Náměstí 2, Prague 160 00, Czech Republic
  • Miroslav Smola
    Miroslav Smola
    Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo Náměstí 2, Prague 160 00, Czech Republic
  • Martin Dračínský
    Martin Dračínský
    Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo Náměstí 2, Prague 160 00, Czech Republic
  • Joshua Smith
    Joshua Smith
    Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo Náměstí 2, Prague 160 00, Czech Republic
    More by Joshua Smith
  • Aleš Marek
    Aleš Marek
    Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo Náměstí 2, Prague 160 00, Czech Republic
    More by Aleš Marek
  • Milan Dejmek
    Milan Dejmek
    Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo Náměstí 2, Prague 160 00, Czech Republic
    More by Milan Dejmek
  • Michal Šála
    Michal Šála
    Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo Náměstí 2, Prague 160 00, Czech Republic
  • Ondrej Gutten
    Ondrej Gutten
    Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo Náměstí 2, Prague 160 00, Czech Republic
  • Lubomír Rulíšek
    Lubomír Rulíšek
    Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo Náměstí 2, Prague 160 00, Czech Republic
  • Barbora Novotná
    Barbora Novotná
    Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo Náměstí 2, Prague 160 00, Czech Republic
    Faculty of Science, Charles University, Albertov 6, Prague 128 00, Czech Republic
  • Andrea Brázdová
    Andrea Brázdová
    Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo Náměstí 2, Prague 160 00, Czech Republic
  • Zlatko Janeba
    Zlatko Janeba
    Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo Náměstí 2, Prague 160 00, Czech Republic
  • Radim Nencka
    Radim Nencka
    Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo Náměstí 2, Prague 160 00, Czech Republic
    More by Radim Nencka
  • Evzen Boura
    Evzen Boura
    Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo Náměstí 2, Prague 160 00, Czech Republic
    More by Evzen Boura
  • Ondřej Páv
    Ondřej Páv
    Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo Náměstí 2, Prague 160 00, Czech Republic
    More by Ondřej Páv
  • , and 
  • Gabriel Birkuš*
    Gabriel Birkuš
    Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo Náměstí 2, Prague 160 00, Czech Republic
    *Email: [email protected]. Phone: (+420) 770-125-014.
Cite this: J. Med. Chem. 2021, 64, 11, 7596–7616
Publication Date (Web):May 21, 2021
https://doi.org/10.1021/acs.jmedchem.1c00301
Copyright © 2021 American Chemical Society

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    Abstract

    Abstract Image

    Cyclic dinucleotides (CDNs) are second messengers that bind to the stimulator of interferon genes (STING) and trigger the expression of type I interferons and proinflammatory cytokines. Here we evaluate the activity of 3′,3′-c-di(2′F,2′dAMP) and its phosphorothioate analogues against five STING allelic forms in reporter-cell-based assays and rationalize our findings with X-ray crystallography and quantum mechanics/molecular mechanics calculations. We show that the presence of fluorine in the 2′ position of 3′,3′-c-di(2′F,2′dAMP) improves its activity not only against the wild type (WT) but also against REF and Q STING. Additionally, we describe the synthesis of the acyloxymethyl and isopropyloxycarbonyl phosphoester prodrugs of CDNs. Masking the negative charges of the CDNs results in an up to a 1000-fold improvement of the activities of the prodrugs relative to those of their parent CDNs. Finally, the uptake and intracellular cleavage of pivaloyloxymethyl prodrugs to the parent CDN is rapid, reaching a peak intracellular concentration within 2 h.

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c00301.

    • Geometries of the models (ZIP)

    • Molecular formula strings (CSV)

    • Synthesis of compounds 12, NMR spectroscopy, DFT calculations, X-ray data, and details of the QM/MM calculations (PDF)

    Accession Codes

    The PDB code for human WT STING with bound compound (Rp)-12 is 6YWB, that for human REF STING with bound compound (Rp)-12 is 6YWA, and that for human WT STING with bound (Rp,Rp)-8 is 7A90. Authors will release the atomic coordinates and experimental data upon publication of the article.

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    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

    Cited By

    This article is cited by 19 publications.

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    2. Marketa Pimkova Polidarova, Lenka Vanekova, Petra Brehova, Milan Dejmek, Zdenek Vavrina, Gabriel Birkus, Andrea Brazdova. Synthetic Stimulator of Interferon Genes (STING) Agonists Induce a Cytokine-Mediated Anti-Hepatitis B Virus Response in Nonparenchymal Liver Cells. ACS Infectious Diseases 2023, 9 (1) , 23-32. https://doi.org/10.1021/acsinfecdis.2c00424
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    13. Noriko Saito-Tarashima, Noriaki Minakawa. Chemistry of Cyclic Dinucleotides and Analogs. 2023, 585-614. https://doi.org/10.1007/978-981-19-9776-1_20
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