Conformation of aromatic-substituted dinucleoside monophosphates: an extension of the base-displacement theory of carcinogenesis.

The conformations of 12 dinucleoside monophosphates containing N4-phenylcytidine (CPh) or N4(beta-naphthyl)cytidine (CbetaN) residues have been studied, using circular dichroic spectroscopy. The following compounds had aqueous spectra resembling their parent compounds, which lacked the modifying aromatic substituent: CPhpU, CbetaNpU, UpCPh, UpCbetaN, CPhpG, CbetaNpG, GpCPh, and CPhpA. The spectra of GpCbetaN and ApCbetaN were almost the reverse of the unmodified compounds, while CbetaNpA and ApCPh were intermediary in character. When the spectra were run in methanol, all major differences between the modified and unmodified compounds disappeared. This result suggested that the differences observed in aqueous solution were the result of stacking interactions between the aromatic ring and a neighboring purine. When the aromatic ring was naphthalene, the modified cytidine occupied the 3'-terminal position, and, when the purine was adenine, the effect was enhanced. These conclusions were supported by a consideration of chemical shifts in the 1H NMR spectra of ApCbetaN, and GpCbetaN, as compared to those of the unmodified compounds and CbetaNpG. A study of molecular models of ApCbetaN and GpCbetaN revealed a unique conformation in which the purine rotates to a syn position, in order to allow a close stacking interaction with the naphthalene ring. No such conformation is available for CbetaNpA and CbetaNpG, and the best partial stacking interaction occurs in a conformation with the purine in the anti conformation. The base-displacement theory of carcinogenesis (Levine, A. F., Fink, L. M., Weinstein, I. B., and Grunberger, D. (1974), Cancer Res. 34, 319) describes the conformational change resulting from the attachment of a bulky aromatic residue at the 8 position of guanine in RNA or DNA, and attributes biological importance to the event. The changes that occur upon substitution of the amino group of cytosine differ in detail from the above, but would be expected to produce similar biological results. Base-displacement effects need not be limited, therefore, to a particular substitution position in a nucleic acid.