DNA base oxidation is considered to be a key event associated with disease initiation and progression in humans. Peroxyl radicals (ROO. ) are important oxidants found in cells whose ability to react with the DNA bases has not been characterized extensively. In this paper, the products resulting from ROO. oxidation of the DNA bases are determined by gas chromatography/MS in comparison with authentic standards. ROO. radicals oxidize adenine and guanine to their 8-hydroxy derivatives, which are considered biomarkers of hydroxyl radical (HO.) oxidations in cells. ROO. radicals also oxidize adenine to its hydroxylamine, a previously unidentified product. ROO. radicals oxidize cytosine and thymine to the monohydroxy and dihydroxy derivatives that are formed by oxidative damage in cells. Identical ROO. oxidation profiles are observed for each base when exposed as deoxyribonucleosides, monohomopolymers and base-paired dihomopolymers. These results have significance for the development, utilization and interpretation of DNA base-derived biomarkers of oxidative damage associated with disease initiation and propagation, and support the idea that the mutagenic potential of N-oxidized bases, when generated in cellular DNA, will require careful evaluation. Adenine hydroxylamine is proposed as a specific molecular probe for the activity of ROO. in cellular systems.
A series of non-natural isosteric analogs of the cationic, ion-pairing, natural amino acids arginine and lysine have been synthesized, characterized with regard to relevant physical parameters, and protected for routine inclusion in Merrifield solid-phase synthesis. The design of these molecules is based on the concept of steric inhibition of solvation, in that judicious placement of alkyl groups can destabilize aqueous ion solvation and favor ion-pairing [see Beeson & Dix (1993) J. Am. Chem. Soc. 115, 10275]. When the residues are substituted for the natural amino acids in biologically active peptides, enhanced ion-pairing of the peptides to their receptors to increase the peptides' biological activities can result. The increased lipophilicity of the non-natural residues can also improve pharmacokinetic parameters and agonist/antagonist behaviors of peptides. While the synthesis of the L-series is described, the D-isomers were also prepared using identical chemistry.
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