Pentafluorophenyl-Phenyl Interactions in Biphenyl-DNA

We prepared and investigated oligonucleotide duplexes of the sequence d(GATGAC(X)nGCTAG)⋅d(CTAGC(Y)nGTCATC), in which X and Y designate biphenyl‐ (bph) and pentafluorobiphenyl‐ (5Fbph) C‐nucleotides, respectively, and n varies from 0–4. These hydrophobic base substitutes are expected to adopt a zipperlike, interstrand stacking motif, in which not only bph/bph or 5Fbph/5Fbph homo pairs, but also 5Fbph/bph mixed pairs can be formed. By performing UV‐melting curve analysis we found that incorporation of a single 5Fbph/5Fbph pair leads to a duplex that is essentially as stable as the unmodified duplex (n=0), and 2.4 K more stable than the duplex with the nonfluorinated bph/bph pair. The Tm of the mixed bph/5Fbph pair was in between the Tm values of the respective homo pairs. Additional, unnatural aromatic pairs increased the Tm by +3.0–4.4 K/couple, irrespective of the nature of the aromatic residue. A thermodynamic analysis using isothermal titration calorimetry (ITC) of a series of duplexes with n=3 revealed lower (less negative) duplex formation enthalpies (ΔH) in the 5Fbph/5Fbph case than in the bph/bph case, and confirmed the higher thermodynamic stability (ΔG) of the fluorinated duplex, suggesting it to be of entropic origin. Our data are compatible with a model in which the stacking of 5Fbph versus bph is dominated by dehydration of the aromatic units upon duplex formation. They do not support a model in which van der Waals dispersive forces (induced dipoles) or electrostatic (quadrupole) interactions play a dominant role. Stable stacking: Fluorophenyl (5Fbph)/phenyl (bph) interactions were studied in the context of DNA duplexes with biaryl base surrogates (denoted X in figure). By using isothermal titration calorimetry (ITC) it was found that the 5Fbph/5Fbph arrangement was the most stable for entropic and not enthalpic reasons, indicating that biaryl recognition in these cases is driven mainly by desolvation.