DNA and other nucleophilic sites on macromolecules (DNA)

DNA and other nucleophilic sites on macromolecules serve as the primary targets for a major class of antineoplastic agents known as alkylating and alkylating-like agents. These targets include electron-rich atoms within DNA bases—most notably the N7 position of guanine—as well as nucleophilic groups on proteins and RNA molecules. When drugs interact with these sites, they form stable covalent bonds or adducts that physically obstruct the machinery required for DNA replication and transcription. This damage often results in intra-strand or inter-strand cross-linking, leading to double-strand breaks and the activation of DNA damage response pathways. Ultimately, the accumulation of unrepaired damage triggers programmed cell death (apoptosis), making these sites critical for treating various malignancies. However, because these interactions are generally non-specific to cancer cells, they are associated with significant systemic toxicities and the risk of secondary cancers.

Other names

Genomic DNACellular macromoleculesNucleophilic targetsDNA basesDeoxyribonucleic acid

Covalent alkylation of nucleophilic moieties (primarily guanine N7), formation of DNA adducts, interstrand and intrastrand cross-linking, and induction of DNA strand breaks leading to apoptosis.