α‑Aminophosphonates in anticancer drug discovery: synthetic strategies, anticancer activities, structure-activity relationships and molecular mechanisms.

α-Aminophosphonates are a promising class of phosphorus-containing compounds in anticancer drug discovery due to their structural similarity to α-amino acids, chemical versatility, and broad biological activities. This review summarizes recent advances (2020-2026) in the development of α-aminophosphonate-based anticancer agents, emphasizing synthetic strategies, structural diversity, biological evaluation, structure-activity relationships (SAR), and mechanisms of action. Particular attention is given to efficient synthetic strategies, the Kabachnik-Fields reaction, the Aza-Pudovik reaction, and other green approaches that facilitate the preparation of structurally diverse analogues. Representative derivatives, including aromatic, peptide-inspired, glycoconjugate, stilbene, triterpenoid, nucleobase, alkaloid, and heterocyclic hybrids, are discussed with respect to their cytotoxic activities against various human cancer cell lines. Mechanistic studies reveal that these compounds induce apoptosis, arrest the cell cycle, and inhibit key cancer-related targets, including topoisomerases, poly(ADP-ribose) polymerase 1 (PARP1), carbonic anhydrase XII, epidermal growth factor receptor (EGFR), and cyclin-dependent kinase 2 (CDK2), while some derivatives also exhibit anti-metastatic activity and the ability to overcome multidrug resistance. Molecular docking and preliminary pharmacokinetic studies further support their potential as lead compounds. Overall, this review highlights recent progress and provides insights to guide the rational design and future development of α-aminophosphonate-based anticancer therapeutics.