DNA and cellular proteins with nucleophilic residues

DNA and cellular proteins with nucleophilic residues represent a broad class of molecular targets for cytotoxic chemotherapy, specifically alkylating agents and platinum-based compounds (StatPearls, 2023). These drugs function by generating highly reactive electrophilic intermediates that form covalent bonds with nucleophilic centers, such as the N7 position of guanine in DNA or the sulfhydryl groups in proteins (NIH, 2022). The resulting DNA adducts and cross-links interfere with essential processes like DNA replication and transcription, ultimately inducing apoptosis in rapidly proliferating cells (PubMed, 2021). While these interactions are the basis for treating various cancers, including lymphomas and solid tumors, they are not specific to malignant cells. Consequently, the modification of these targets in healthy tissues leads to significant side effects such as myelosuppression, infertility, and the potential for secondary malignancies (Wikipedia, 2024). Understanding the repair mechanisms for these modifications, such as the MGMT pathway, is crucial for predicting drug efficacy and resistance (PubMed, 2020).

Other names

Nucleophilic sites in DNA and proteinsAlkylation targetsCellular nucleophilesDNA and protein nucleophiles

Alkylating agents and platinum compounds act as electrophiles that react with nucleophilic sites on DNA (primarily the N7 position of guanine) and proteins (sulfhydryl, amino, and carboxyl groups), forming covalent adducts and cross-links that inhibit DNA replication and transcription (StatPearls, 2023; NIH, 2022).