Cellular nucleophiles in DNA, RNA, and proteins

Cellular nucleophiles in DNA, RNA, and proteins represent the collective molecular targets for electrophilic cytotoxic agents, primarily alkylating drugs and platinum coordination complexes. These targets include electron-rich sites such as the nitrogen and oxygen atoms in nucleic acid bases and the sulfur or nitrogen atoms in amino acid side chains (PubChem, "Alkylating Agents"). The interaction typically involves the formation of a strong covalent bond between the drug and the nucleophile, most notably at the N7 position of guanine residues in DNA (NIH, National Cancer Institute). Such modifications result in DNA adducts, intra-strand or inter-strand cross-links, and DNA-protein cross-links, which physically obstruct the machinery required for DNA replication and RNA transcription. This disruption triggers cellular stress responses and leads to programmed cell death, making these nucleophiles critical targets in the treatment of various cancers and certain autoimmune conditions. However, because these nucleophilic sites are ubiquitous in all cells, drugs targeting them often lack specificity, leading to significant toxicities such as bone marrow suppression and the potential for secondary malignancies. Monitoring biomarkers like MGMT expression can help predict therapeutic resistance, as this enzyme repairs specific types of DNA alkylation damage (PubMed, PMID: 11412163).

Other names

Biological nucleophilesNucleophilic sites in macromoleculesCellular macromolecules

Covalent modification of nucleophilic sites in DNA, RNA, and proteins, leading to DNA cross-linking and inhibition of replication and transcription.