C-Linked 8-aryl guanine nucleobase adducts: biological outcomes and utility as fluorescent probes

Abstract

Aryl radical species derived from enzymatic transformations of aromatic mutagens preferentially react at the 8-site of the guanine (G) nucleobase to afford carbon-linked 8arylG adducts. The resulting lesions possess altered biophysical and genetic coding properties compared to the precursor G nucleoside in B-form DNA. Unlike other adducts, these lesions also possess useful fluorescent properties, since direct attachment of the 8aryl ring extends the purine π-system to afford G mimics with red-shifted excitation maxima and emission that can be sensitive to the microenvironment of the 8arylG base within nucleic acid structures. In B-form DNA, 8arylG adducts are disruptive to duplex formation because they prefer to adopt the syn-conformation about the bond connecting the nucleobase to the deoxyribose backbone, which perturbs Watson–Crick (WC) H-bonding with the opposing cytosine (C). Thus, in a B-form duplex, the emissive properties of 8arylG adducts can be employed as a tool to provide insight into adduct conformation, which can be related to their biological outcomes. However, since Gs preferentially adopt the syn-conformation in left-handed Z-DNA and antiparallel G-quadruplex (GQ) structures, 8arylG lesions can be inserted into syn-G positions without disrupting H-bonding interactions. In fact, 8arylG lesions can serve as ideal fluorescent probes in an antiparallel GQ because their emission is sensitive to GQ folding. This perspective outlines recent developments in the biological implications of 8arylG formation together with their utility as fluorescent G analogs for use in DNA-based diagnostic systems.