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Investigation of the function of the new epigenetic bases requires the development of stabilized analogues that are stable during base excision repair (BER). Here we report the synthesis of 2′-(R)-fluorinated versions of the phosphoramidites of 5-methylcy

The possible role of DNA i-motif structures in telomere biology and in the transcriptional regulation of oncogene promoter regions is supported by several recent studies. Herein we investigate the effect of four cytidine nucleosides (and combinations thereof) on i-motif structure and stability, namely 2′-deoxycytidine (dC), 2′-deoxy-5-methyl-cytidine (5-Me-dC), 2′-deoxy-2′-fluoro-arabinocytidine (2′F-araC), and 2′-deoxy-2′-fluoro-5-methyl-arabinocytidine (5-Me-2′F-araC). The base pair 5-Me-2′F-araC:2′F-araC produced i-motifs with a pH1/2 (“pKa”) value that closely matches physiological pH (7.34±0.3). NMR analysis of the most stable telomeric sequence (HJ-2) at pH 7.0 indicated that the structure is stabilized by hybrid 5-Me-dC:2′F-araC hemiprotonated base pairs and therefore highlights the significance of the interplay between base and sugar modifications on the stability of i-motif structures.