A Cationic Cyclophane That Forms a Base-Pair Open Complex with RNA Duplexes

It is now well-established that synthetic organic cations can interact with the helical conformations of DNA and RNA and can stabilize these structures. Such interactions can also perturb the function of nucleic acids, generally through modification of the interaction of nucleic acids with proteins and, thus, can be of significant therapeutic benefit against selected cells or organisms. We have investigated by Tm and viscosity studies and by CD and 1H NMR spectra the interactions of tetracationic azoniacyclophanes, CPnn, where nn is the number of methylene groups (from 3 to 6) in the linking chains, with DNA and RNA polymers of the same sequence. All the compounds stabilize the DNA polymers, but, in a surprising result, the compounds either stabilize RNA duplexes or alternatively cause base-pair opening in RNA duplexes depending on the size of the cyclophane and the solution conditions. With RNA polymers containing A−U base pairs, the largest cyclophane, CP66, specifically binds the adenine bases into its cavity and can cause complete denaturation of the RNA at high concentrations. The NMR shift changes observed both for CP66 and the adenine base in the polymer predict an inclusion complex with the base in the cavity of CP66. These shift values can be related to those measured earlier with complexes between the same macrocycle and several adenine derivatives (Schneider, H.-J.; Blatter, T.; Palm, B.; Pfingstag, U.; Rüdiger, V.; Theis, I. J. Am. Chem. Soc. 1992, 114, 7704−7708) and reflect the NMR anisotropy effects of the aromatic units both in host and guest. The different effects of the compounds on DNA and RNA are caused by significant differences in their interactions with the duplex and single-stranded states of the nucleic acids.