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

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    SYSNO ASEP0543611
    Document TypeJ - Journal Article
    R&D Document TypeJournal Article
    Subsidiary JČlánek ve WOS
    TitleSynthesis and Biological Evaluation of Phosphoester and Phosphorothioate Prodrugs of STING Agonist 3′,3′-c-Di(2′F,2′dAMP)
    Author(s) Pimková Polidarová, Markéta (UOCHB-X) ORCID
    Břehová, Petra (UOCHB-X) RID, ORCID
    Kaiser, Martin Maxmilian (UOCHB-X) RID, ORCID
    Smola, Miroslav (UOCHB-X) ORCID
    Dračínský, Martin (UOCHB-X) RID, ORCID
    Smith, Joshua (UOCHB-X)
    Marek, Aleš (UOCHB-X) RID, ORCID
    Dejmek, Milan (UOCHB-X) RID, ORCID
    Šála, Michal (UOCHB-X) RID, ORCID
    Gutten, Ondrej (UOCHB-X) RID, ORCID
    Rulíšek, Lubomír (UOCHB-X) RID, ORCID
    Novotná, Barbora (UOCHB-X) ORCID
    Brázdová, Andrea (UOCHB-X) ORCID
    Janeba, Zlatko (UOCHB-X) RID, ORCID
    Nencka, Radim (UOCHB-X) RID
    Bouřa, Evžen (UOCHB-X) ORCID
    Páv, Ondřej (UOCHB-X) RID, ORCID
    Birkuš, Gabriel (UOCHB-X) ORCID
    Source TitleJournal of Medicinal Chemistry - ISSN 0022-2623
    Roč. 64, č. 11 (2021), s. 7596-7616
    Number of pages21 s.
    Languageeng - English
    CountryUS - United States
    KeywordsDNA sensor ; interferon genes ; cyclic GMP-AMP
    OECD categoryMedicinal chemistry
    R&D ProjectsEF16_019/0000729 GA MŠk - Ministry of Education, Youth and Sports (MEYS)
    GA20-08772S GA ČR - Czech Science Foundation (CSF)
    Method of publishingLimited access
    Institutional supportUOCHB-X - RVO:61388963
    UT WOS000662187100032
    EID SCOPUS85108021486
    DOI10.1021/acs.jmedchem.1c00301
    AnnotationCyclic 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.
    WorkplaceInstitute of Organic Chemistry and Biochemistry
    ContactMarie Odehnalová,marie.odehnalova@uochb.cas.cz Tel.: 220 183 418 ; Viktorie Chládková, viktorie.chladkova@uochb.cas.cz, Tel.: 232 002 434
    Year of Publishing2022
    Electronic addresshttps://doi.org/10.1021/acs.jmedchem.1c00301
Number of the records: 1