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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.

The dithiadiazolyl radical p-BrC 6 F 4 CNSSN • 2 retains its monomeric nature in the solid state; variable temperature magnetic studies on 2 indicate Curie-Weiss behaviour (q = 227 K) above 60 K with an effective magnetic moment of 1.45 m B at room temperature; the absence of long-range magnetic order down to 1.8 K is attributed to the low dimensionality of the magnetic exchange pathway predicted on the basis of the inter-molecular S…N interactions.

Two dithiadiazolyl radicals, p-NCC6F4CNSSN and p-BrC 6 F4CNSSN, have recently been found to be paramagnetic in the solid state. While the (3-phase of the first one exhibits spontaneous magnetization below 36 K, the second one shows a paramagnetic character in the solid state. The spin density distribution in these radicals is examined through continuous-wave electron paramagnetic resonance and electron spin echo envelope modulation spectroscopies. Hyperfine correlation sublevel spectroscopy provides information about the interaction of the unpaired spin with F and N nuclei. A signal coming from the interaction with Br nucleus is also detected. The superhyperfine coupling constants of the unpaired electron with the magnetic nuclei are obtained and values of the corresponding spin densities, f and f -f, can be estimated in the isolated radicals. Spin density distribution has also been calculated in both molecules with density functional theory, being in excellent agreement with those determined from the spectra. The spin density is mainly concentrated in the dithiadiazolyl ring, but some spin density is observed on the fluorinated aromatic rings. They also provide a strong basis to understand the differences of the magnetic behavior of both molecules in terms of their respective packing in the solid state.