Structural Effects of Incorporation of 2'‐Deoxy‐2'2'‐Difluorodeoxycytidine (Gemcitabine) in A‐ and B‐Form Duplexes

We report the structural effect of 2'‐deoxy‐2',2'‐difluorocytidine (dFdC) insertions in the DNA strand of a DNA : RNA hybrid duplex and in a self‐complementary DNA : DNA duplex. In both cases, the modification slightly destabilizes the duplex and provokes minor local distortions that are more pronounced in the case of the DNA : RNA hybrid. Analysis of the solution structures determined by NMR methods show that dFdC is an adaptable derivative that adopts North type sugar conformation when inserted in pure DNA, or a South sugar conformation in the context of DNA : RNA hybrids. In this latter context, South sugar pucker favors the formation of a 2'F⋅⋅H8 attractive interaction with a neighboring purine, which compensates the destabilizing effect of base pair distortions. These interactions share some features with pseudohydrogen bonds described previously in other nucleic acids structures with fluorine modified sugars. 2'‐Deoxy‐2',2'‐difluorocytidine (gemcitabine) is an adaptable nucleotide derivative that can adopt a North type sugar conformation when inserted in pure DNA (B‐form helix), or a South sugar conformation in the context of DNA : RNA hybrids (A‐form helix).