DNA adduct profiles: chemical approaches to addressing the biological impact of DNA damage from small molecules

Diverse small molecules alkylate DNA and form covalently linked adducts that can influence crucial biological processes, contributing to toxicity and mutation. Understanding the chemical reactivity dictating DNA alkylation and interactions of adducts with biological pathways can impact disease prevention and treatment. The ambident reactivity of DNA-alkylating small molecules, and of DNA itself, often results in formation of multiple adducts. Determining which structures impart biological responses is important for understanding the underlying relationships between small-molecule structure and biology. With application of sensitive and structure-specific experimental and analytical methodology, such as heteronuclear NMR spectroscopy and mass spectrometry, there are increasing numbers of studies that evaluate DNA alkylation from the perspective of resulting adduct profiles. DNA adduct profiles have been examined for both exogenous and endogenous reactive small molecules. Examples of recent findings are in the areas of tobacco-specific carcinogens, lipid peroxidation products, environmental and dietary chlorophenols, and natural-product-derived antitumor therapies. As more profile data are obtained, correlations with biological impact are being observed that would not be identified by a simplified single agent/single adduct approach.