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Article Abstract
Herein 2-cyanoethoxy-N,N,N',N'-tetraisopropyl-phosphorodiamidite(10, P, 3.5 eq.) could synergistically react with 3',5'-dihydroxyl groups in a dinucleotide(P) at the cyclization step for the synthesis of cyclic dinucleotides (CDNs) (c-di-GMP, cGAMP etc.) and their phosphorothioated analogues. A dynamic P-P coordination mechanism has been proposed for the cyclization procedure which is confirmed by the variant P NMR data and molecular simulation. Among the mono-phosphorothioated CDNs, two stereoisomers showed different capacity for STING activation and the reason was predicted by molecular modeling. While compound 12b showed most potent ability to elicit cytokines (IFNβ, IL-6, Cxcl9 and Cxcl10) induction compared to another stereoisomer. Also, 12b significantly inhibited the tumor growth in the EO771 model with both 0.1 μg (i.t.) and 2 μg (i.v.) administration through the aid of a Mix delivery system developed by our group, and achieved a 31% long-term survival rate of tumor-bearing mice. 12b/Mix significantly improved the percentage of CD8 or CD4 effector memory T (Tem, CD44CD62L) cells and CD8 central memory T (Tcm, CD44CD62L) cells in the blood of EO771 mice, inducing the immune memory against EO771 tumor cells. Relatively lower dose regimens of 12b(0.1 μg)/Mix displayed better tumor suppression by more potent STING pathway activation and higher levels of cytokines induction in the tumor.
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| http://dx.doi.org/10.1016/j.ejmech.2022.115053 | DOI Listing |
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