DNA and RNA nucleophilic sites

DNA and RNA nucleophilic sites are the primary molecular targets for alkylating agents and platinum-based antineoplastics (StatPearls, 2023). These sites, particularly the N7 and O6 positions of guanine, possess high electron density, making them susceptible to covalent modification by electrophilic drug intermediates (NCI, 2024). The resulting DNA adducts and cross-links (both intra-strand and inter-strand) physically distort the DNA double helix, which stalls replication forks and inhibits RNA polymerase activity (Alberts et al., 2014). This damage triggers cellular stress responses and, if unrepaired, leads to p53-mediated apoptosis, which is the basis for their efficacy in treating various cancers (Goodman & Gilman, 2018). However, because these nucleophilic sites are present in the genomes of both malignant and healthy cells, these agents lack inherent tumor specificity, leading to significant toxicities in rapidly dividing normal tissues such as the bone marrow and gastrointestinal tract (StatPearls, 2023).

Other names

Nucleic acid nucleophilic centersDNA basesGuanine N7 siteElectrophile-sensitive sites in nucleic acidsDNA adduct sites

Covalent attachment of alkyl or platinum groups to nucleophilic centers (primarily the N7 position of guanine), resulting in the formation of DNA adducts and cross-links that physically obstruct DNA replication and transcription (StatPearls, 2023; NCI, 2024).