2- and 4-quinolones as emerging anticancer scaffolds: Recent synthetic developments, SAR insights, and mechanistic...

Quinolones have recently gained significant interest in oncology due to their structural versatility and broad pharmacological potential. Their modifiable scaffold makes them attractive candidates for anticancer drug development, enabling optimization of potency, selectivity, and pharmacokinetic properties. This review highlights recent advances in the synthesis of 2-quinolone and 4-quinolone derivatives, with an emphasis on emerging strategies such as metal-catalyzed reactions, photochemical approaches, base-mediated transformations, and metal-free methodologies. We summarize contemporary structure-activity relationship (SAR) studies that elucidate features governing anticancer activity in quinolone-based compounds. Additionally, we discuss mechanistic evidence demonstrating that quinolones exert antitumor effects through diverse molecular pathways, including topoisomerase inhibition, apoptosis induction, cell-cycle arrest, G-quadruplex stabilization, HDAC inhibition, modulation of miRNA processing, and regulation of key oncogenic signaling networks such as EGFR/PI3K/mTOR and S1P. The current landscape of quinolone-derived anticancer agents in preclinical and clinical development is also reviewed. Overall, this article provides a comprehensive and translational perspective on the synthetic advances, SAR insights, and mechanistic foundations supporting the development of 2- and 4-quinolone scaffolds as promising anticancer therapeutics.