Quercetin and its Derivatives as Targeted Potential Anticancer Agents: Insight into Synthesis, Mechanism, and SAR Approaches.

Abstract

Introduction: Cancer remains a major global health challenge, with GLOBOCAN 2022 estimating around 20 million current cases and 9.7 million deaths, projected to surpass 35 million by 2050. This review aims to consolidate two decades of preclinical and translational evidence on quercetin, a naturally occurring pentahydroxyflavone widely distributed across fruits, vegetables, and other plant sources, as a multitargeted candidate for cancer prevention and therapy, with particular focus on its semisynthetic derivatization, mechanisms of action, and structure-activity relationships.

Methods: This review compiles and critically examines preclinical studies investigating quercetin's chemical structure, pharmacological mechanisms, and therapeutic efficacy across a broad range of cancer types, with breast cancer receiving primary emphasis owing to the depth and mechanistic specificity of the available MCF- 7-centered literature, followed by substantial coverage of blood, lung, prostate, colon, and bladder cancers. The synthesis additionally incorporates SAR analysis of semisynthetic derivatives, relevant patent literature, computational studies, and available clinical evidence.

Results: Quercetin exhibits significant anticancer potential through apoptosis induction, modulation of AMPK/mTOR signaling, and suppression of cancer stem cell (CSC) markers (CD44, CD133). Studies reveal its broad efficacy in breast, colon, and lung cancers, potent cytotoxicity against MCF-7 cells, and synergistic effects in combination with standard chemotherapeutics. Quercetin and its derivatives also counter multidrug resistance by modulating P-gp and BCRP transporters and enhance redox balance via redox-active analogs. Structure- activity relationship analysis identifies selective O-alkylation, methylation, and etherification, particularly at the 3- and 7-positions, as key strategies for enhancing potency and selectivity over native quercetin.

Discussion: The multitargeted mechanisms of quercetin, combined with structure-guided semisynthetic optimization, position it as a promising candidate for precision oncology. Computational approaches including molecular docking and network pharmacology further support and extend these mechanistic findings, while emerging clinical studies provide early, if still preliminary, validation of quercetin's translational potential.

Conclusion: Quercetin offers significant therapeutic promise as a naturally derived, semi synthetic tunable compound in precision oncology. Future research should prioritize formulation optimization, expanded clinical investigation, and integration of computational target-prediction tools to fully realize its anticancer potential.