Stereochemical properties of nucleosides alkylated by activated carcinogens.
An initial stage in the mechanism of chemical carcinogenesis by "activated" carcinogenic polycyclic aromatic hydrocarbons is believed to involve alkylation of DNA. However, very high (atomic) resolution studies of alkylated DNA are not technically feasible at this time, and therefore the detailed, high-resolution three-dimensional structures of portions of alkylated DNA have been determined. The initial phase of this study (reported here) has involved the preparation of a series of adenosines and 2'-deoxyadenosines substituted at N6 by related aralkyls of differing carcinogenic potential. We report here the crystal structure determinations of four of these compounds: Compound 1, N6-(anthracenyl-9-methyl)adenosine; Compound 2, N6-(10-methyl-anthracenyl-9-methyl)adenosine; Compound 3, N6-[12-methyl-benz(a)anthracenyl-7-methyl]adenosine; and Compound 5, N6-(10-methylanthracenyl-9-methyl)-2'-deoxyadenosine. Results are compared with those for a previously published analysis Compound 6, N6-[12-methylbenz(a)anthracenyl-7-methyl]-2'-deoxyadenosine. Several results of structural interest have emerged. All five compounds have the syn-conformational relationship between the sugar (ribose or 2'-deoxyribose) and the base (adenine), in contrast to the anti arrangement in B-DNA and in nonalkylated nucleosides. In four of the five compounds, there is an intramolecular hydrogen bond between the 5'-hydroxyl group and adenine. However, in the fifth molecule, this hydrogen bond is not found, and yet the conformation is syn. This indicates that formation of this internal hydrogen bond is not a prerequisite for the adoption of the syn-conformation. In general, the overall conformations of all five compounds are similar, the base lying approximately perpendicular to the polycyclic aromatic ring system. The packing of molecules in the unit cell is also of interest because it consists of alternations of adenine and polycyclic aromatic ring systems in columns through the crystal, indicating that this may serve as a model for the interaction with DNA. The oxygen atom of the sugar ring points towards the hydrocarbon ring system of another molecule. It is premature at this stage of our study to speculate as to the effects of alkylation on the conformational properties of either RNA or DNA. The only comment that appears justified is that the propensity of these adducts to adopt the syn-conformation may be indicative of a preference of alkylated DNA for the Z-conformation (even if the form that is initially attacked is B-DNA).(ABSTRACT TRUNCATED AT 400 WORDS)
D000477:Alkylating Agents; D000478:Alkylation; D002273:Carcinogens; D004247:DNA; D006860:Hydrogen Bonding; D007202:Indicators and Reagents; D008958:Models, Molecular; D008968:Molecular Conformation; D009690:Nucleic Acid Conformation; D009705:Nucleosides / Q000138:chemical synthesis; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000477:Alkylating Agents; D002273:Carcinogens; D007202:Indicators and Reagents; D009705:Nucleosides; D004247:DNA