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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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    0543611 - ÚOCHB 2022 RIV US eng J - Journal Article
    Pimková Polidarová, Markéta - Břehová, Petra - Kaiser, Martin Maxmilian - Smola, Miroslav - Dračínský, Martin - Smith, Joshua - Marek, Aleš - Dejmek, Milan - Šála, Michal - Gutten, Ondrej - Rulíšek, Lubomír - Novotná, Barbora - Brázdová, Andrea - Janeba, Zlatko - Nencka, Radim - Bouřa, Evžen - Páv, Ondřej - Birkuš, Gabriel
    Synthesis and Biological Evaluation of Phosphoester and Phosphorothioate Prodrugs of STING Agonist 3′,3′-c-Di(2′F,2′dAMP).
    Journal of Medicinal Chemistry. Roč. 64, č. 11 (2021), s. 7596-7616. ISSN 0022-2623. E-ISSN 1520-4804
    R&D Projects: GA MŠk(CZ) EF16_019/0000729; GA ČR(CZ) GA20-08772S
    Institutional support: RVO:61388963
    Keywords : DNA sensor * interferon genes * cyclic GMP-AMP
    OBOR OECD: Medicinal chemistry
    Impact factor: 7.446, year: 2020
    https://doi.org/10.1021/acs.jmedchem.1c00301

    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.
    Permanent Link: http://hdl.handle.net/11104/0320799

     
     
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