Natural Flavonoids: Myricetin and Its Derivatives as Emerging Therapeutics, SAR and Molecular Target Analysis

Abstract

Myricetin is a flavonol found naturally with a high degree of polyhydroxylation, with a very high antioxidant activity (ORAC 4.3 units). It has become a polypharmaceutical therapeutic candidate in cancer therapy, neurodegenerative, metabolic, and heart disease. The review is a synthesis of the structure-activity relationships (SAR) of myricetin and its derivatives, describing the key role of the pyrogallol B-ring moiety in the provision of a 60 % antioxidant ability enhancement. Specific structural changes, such as methylation, glycosylation, acylation, and semi-synthetic heterocyclic conjugation, result in compounds with 50-100-fold potency increases and better metabolic stability, though with a reduced antioxidant activity at orthodox assays. Molecularly, myricetin exhibits multitarget kinase engagement (PI3K, Akt, mTOR, JAK1, Src), context-dependent MAPK modulation, robust NF-κB/STAT3 suppression, and Nrf2/ARE antioxidant response activation. Mechanistically, myricetin induces bifocal cell cycle arrest (G0/G1 via cyclin D1 downregulation and p21/p27 accumulation; G2/M via cyclin B1 suppression), intrinsic and extrinsic apoptotic pathway activation, and ROS-dependent pro-death signaling in transformed cells. Preclinical studies show that it has great efficacy in triple-negative breast cancer (IC₅₀ = 22.70-51.43 μg/mL; selectivity index = 63.64), hepatocellular carcinoma (92% tumour reduction), and Alzheimer's disease models, where tau phosphorylation is suppressed, and synaptic proteins are restored. However, myricetin has extremely low oral bioavailability (9.62-9.74%), chemical instability (t₁/₂ = 0.55 hours), and extensive Phase II metabolism, which requires sophisticated delivery plans. Nano formulations have realized 4-25-fold enhancements in bioavailability. This review would make myricetin a scientifically proven natural lead compound with significant translational potential, provided that optimization of bioavailability and rational derivatives are done systematically.