Progress on quinoline‑based antitumour agents: Mechanistic insights and optimization strategies (Review)

Quinoline derivatives are a class of heterocycles featuring a fused benzene‑pyridine scaffold that have attracted notable interest in anticancer drug discovery owing to their favourable physicochemical properties, structural versatility and broad biological activities. Accumulating evidence indicates that quinoline‑based compounds exert antitumour effects through several targets and pathways, including via epigenetic regulation, interference with DNA topology, inhibition of signalling pathways, immune modulation, induction of autophagy and targeting of the cytoskeleton. Structure‑activity relationship (SAR) analyses demonstrate that the electronic effects and steric configurations of substituents on the quinoline ring critically determine potency, selectivity and metabolic stability. In particular, oxygenated, halogenated and strongly electron‑withdrawing groups, as well as nitrogen‑containing heterocyclic substituents, enhance hydrophobic interactions or hydrogen bonding with biological targets, thereby improving inhibitory efficacy. Consequently, the quinoline scaffold has emerged as a rated structural motif in anticancer lead compound discovery. Multidimensional optimisation strategies have been proposed to improve the pharmacokinetic profiles and clinical applicability of quinoline derivatives. Nanocarriers and smart stimuli‑responsive delivery systems markedly enhance solubility, circulation time and tumour targeting, whereas prodrug approaches employing enzyme‑sensitive, pH‑responsive or redox‑activated linkers enable selective activation at tumour sites. Combination therapies also exploit the multi‑pathway activity of quinoline derivatives, enhancing antitumour responses and delaying resistance when combined with immunotherapy, chemotherapy or radiotherapy. Furthermore, artificial intelligence and machine learning approaches have shown increasing utility in virtual screening, quantitative structure‑activity relationship modelling and multi‑objective optimisation, accelerating the identification of potent, low toxicity and synthetically accessible candidates. Overall, quinoline derivatives offer systemic advantages as multi‑target anticancer agents. The present review summarises recent advances in molecular mechanisms, SAR insights and drug design strategies, providing a comprehensive framework for advancing quinoline‑based agents towards next‑generation precision anticancer therapies.