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

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Abstract
The conformations of 12 dinucleoside monophosphates containing N4-phenylcytidine (CPh) or N4(.beta.-naphthyl)cytidine (C.beta.N) residues were studied, using circular dichroic spectroscopy. The following compounds had aqueous spectra resembling their parent compounds, which lacked the modifying aromatic substituent: CPhpU, C.beta.NpU, UpCPh, UpC.beta.N, CPhpG, C.beta.NpG, GpCPh and CPhpA. The spectra of GpC.beta.N and ApC.beta.N were almost the reverse of the unmodified compounds, while C.beta.NpA and ApCPh were intermediary in character. When the spectra were run in methanol, all major differences between the modified and unmodified compounds disappeared. The differences observed in aqueous solution were probably 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 ApC.beta.N, and GpC.beta.N, as compared to those of the unmodified compounds and C.beta.NpG. A study of molecular models of ApC.beta.N and GpC.beta.N 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 C.beta.NpA and C.beta.NpG, 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), describes the conformational changes 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 on 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 to a particular substitution position in a nucleic acid.

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