A Bimolecular Simultaneous Macrocyclization Strategy to Synthesize Cyclic Dinucleotide Analogues with Internucleoside
Di Xie1, Jiwei Tang1, Tingting Zhang1
1Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Henan Key Laboratory of Organic Functional Molecule and Drug Innovation, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, P. R. China.
None:
Internucleoside guanidinium linkages are excellent mimics of phosphodiesters and have been used to improve the properties of oligonucleotides. Herein we reported a step economic bimolecular simultaneous macrocyclization (BSM) protocol to prepare cyclic dinucleotide (CDN) analogues with guanidinium linkages. Compared with the 26 steps protocol reported in literature, the current method could provide CDN analogues with internucleoside guanidinium linkages in 9 steps, and the key intermediate prepared in the first 3 steps could be shared to prepare CDN analogues with different nucleobases. The CDN analogues were investigated as STING agonist in mammalian cells, and biofilm inhibitor in Gram-positive and Gram-negative bacteria. Compound 13c showed the best biofilm inhibition in Escherichia coli, with the inhibition rate of 54% at the concentration of 78 μM.
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