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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 ASEP 0543611 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Synthesis 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, ORCID
Bouřa, Evžen (UOCHB-X) ORCID
Páv, Ondřej (UOCHB-X) RID, ORCID
Birkuš, Gabriel (UOCHB-X) ORCIDSource Title Journal of Medicinal Chemistry. - : American Chemical Society - ISSN 0022-2623
Roč. 64, č. 11 (2021), s. 7596-7616Number of pages 21 s. Language eng - English Country US - United States Keywords DNA sensor ; interferon genes ; cyclic GMP-AMP OECD category Medicinal chemistry R&D Projects EF16_019/0000729 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) GA20-08772S GA ČR - Czech Science Foundation (CSF) Method of publishing Limited access Institutional support UOCHB-X - RVO:61388963 UT WOS 000662187100032 EID SCOPUS 85108021486 DOI 10.1021/acs.jmedchem.1c00301 Annotation 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. Workplace Institute of Organic Chemistry and Biochemistry Contact asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Viktorie Chládková, Tel.: 232 002 434 Year of Publishing 2022 Electronic address https://doi.org/10.1021/acs.jmedchem.1c00301
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