Flavonoids and semi-synthetic derivatives targeting oncogenic inflammation: dose-response relationships, toxicological profiles, and synergistic potential.

Chronic inflammation represents a critical driver of tumorigenesis and malignant progression, with nuclear factor-kappa B (NF-κB) and cyclooxygenase-2 (COX-2) Signaling pathways serving as central mediators of the cancer-inflammation axis. Flavonoids, a diverse class of polyphenolic natural products, have emerged as promising multi-targeted agents capable of disrupting inflammatory networks that sustain tumor growth, therapeutic resistance, and immune evasion. This comprehensive review examines the molecular pharmacology, structure-activity relationships, toxicological profiles, and synergistic potential of novel flavonoid derivatives in oncological applications. Preclinical evidence demonstrates that flavonoids simultaneously inhibit NF-κB transcriptional activity, suppress COX-2 expression, modulate receptor tyrosine kinases, and reshape the immunosuppressive tumor microenvironment through effects on myeloid-derived suppressor cells and regulatory T cells. Structure-activity relationship analyzes reveal that hydroxylation patterns, particularly the B-ring catechol moiety, and strategic chemical modifications including prenylation and methylation substantially enhance anti-inflammatory potency and metabolic stability. Advanced nanoparticle-based delivery systems have overcome bioavailability limitations, enabling therapeutic tissue concentrations with favourable pharmacokinetic profiles. Synergistic interactions with chemotherapeutic agents and immune checkpoint inhibitors have been documented in preclinical models and early-phase clinical trials, with meta-analyzes suggesting survival benefits in selected cancer types. However, dose-limiting hepatotoxicity, complex cytochrome P450-mediated drug interactions, and inter-individual pharmacokinetic variability necessitate careful toxicological evaluation and precision dosing strategies. Current clinical development pipelines employing biomarker-enriched patient selection and adaptive trial designs are establishing therapeutic windows essential for phase III registration studies. Flavonoids offer significant promise as adjunctive anti-inflammatory cancer therapeutics when integrated within comprehensive, toxicology-informed clinical development frameworks.