Journal
JOURNAL OF ORGANIC CHEMISTRY
Volume 88, Issue 6, Pages 3599-3614Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.joc.2c02796
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This manuscript describes a chemical strategy to preorganize a trinucleotide subunit in a conformation suitable for base pairing, using bis-phosphonate esters bridging hydrocarbon tethers to create macrocyclic analogues. The synthesis and incorporation of eight P-stereoisomers of these analogues into oligonucleotides (ONs) is described, and their effect on hybridization kinetics with RNA is characterized. The size of the macrocyclic tether and configuration at phosphorus significantly influenced the on-rates and off-rates of the modified ONs. The results highlight the potential of backbone-constrained macrocyclic nucleic acid analogues in modulating hybridization kinetics.
We recently described a chemical strategy to pre organize a trinucleotide subunit in a conformation suitable for Watson-Crick base pairing for modulating the binding kinetics of single-stranded oligonucleotides (ONs) using bis-phosphonate esters bridging hydrocarbon tethers to provide 11-and 15 membered macrocyclic analogues. In this manuscript, we describe the synthesis of all eight P-stereoisomers of macrocyclic 12-, 13-, 14-, and 16-membered hydrocarbon-bridged nucleotide trimers, their incorporation into ONs, and biophysical characterization of the modified ONs. The size of the macrocyclic tether and configuration at phosphorus had profound effects on hybridization kinetics. ONs containing 12-and 13-membered rings exhibited faster on-rates (up to 5-fold) and off-rates (up to 161-fold). In contrast, ONs using the larger ring size macrocycles generally exhibited smaller changes in binding kinetics relative to unmodified DNA. Interestingly, several of the analogues retained significant binding affinity for RNA based on their dissociation constants, despite being modestly destabilizing in the thermal denaturation experiments, highlighting the potential utility of measuring dissociation constants versus duplex thermal stability when evaluating novel nucleic acid analogues. Overall, our results provide additional insights into the ability of backbone-constrained macrocyclic nucleic acid analogues to modulate hybridization kinetics of modified ONs with RNA.
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