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

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

  • J Med Chem. 2021 Jun 10;64(11):7596-7616. doi: 10.1021/acs.jmedchem.1c00301.
Markéta Pimková Polidarová 1 2,  Petra Břehová 1,  Martin Maxmilian Kaiser 1,  Miroslav Smola 1,  Martin Dračínský 1,  Joshua Smith 1,  Aleš Marek 1,  Milan Dejmek 1,  Michal Šála 1,  Ondrej Gutten 1,  Lubomír Rulíšek 1,  Barbora Novotná 1 2,  Andrea Brázdová 1,  Zlatko Janeba 1,  Radim Nencka 1,  Evzen Boura 1,  Ondřej Páv 1,  Gabriel Birkuš 1
Affiliations

Affiliations

  • 1 Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo Náměstí 2, Prague 160 00, Czech Republic.
  • 2 Faculty of Science, Charles University, Albertov 6, Prague 128 00, Czech Republic.
PMID: 34019405 DOI: 10.1021/acs.jmedchem.1c00301
Abstract

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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