Introduction

Myricetin is a naturally occurring favone in fruits, vegetables, teas, and plant wines. Both the free and glycosidic bond forms of myricetin exist with hexahydroxyl substitutions at the 3,3′, 4′,5, 5′, and 7 positions. It is less soluble in water but readily dissolves in organic solvents such as acetone, dimethylformamide, dimethylacetamide, tetrahydrofuran, and several primary aqueous media. The degradation of the compound is pH and temperature-dependent, and it is highly stable at pH2. The researchers initially isolated myricetin in light yellow crystal (Figure 1)form from the bark of the plant Myrica nagi Thunb. (Myricaceae) hundreds of years ago in India. It was also isolated from the aerial part of the Polygonumbellardii All. Strawberry, spinach, Euphorbia tirucalli L., Cyperusrotundus L. rhizomes, and Trigonella foenum-graecum seed extract had the most amazing myricetin content among the Polygonaceae in methanol extract. It contains pyrogallol B-ring and hydroxylated structure, which is highly responsible for its various biological activities compared to other favonols. The dietary consumption of myricetin decreases the risk of cancer because of its numerous antitumour properties.[1-2]

Synthesis methods of myricetin [2]

Biosynthesis of myricetin

In myricetin biosynthesis, the plant typically follows the phenylpropanoid biosynthetic mechanism. The mechanism begins with converting phenylalanine to cinnamic acid, catalysed by the phenylalanine ammonia-lyase (PAL). The cinnamic acid was further catalysed by an enzyme cinnamate 4-hydroxylase (C4H) to generate p-coumaric acid and then 4-coumaroly-CoA. Natural phenylpropanoids, such as cumarins, stilbenes, and favonoids, are formed by condensing  three molecules of malonyl-CoA and one molecule of p-coumaroyl CoA that further changed into naringenin chalcone with the help of chalcone synthase (CHS). This enzyme is regarded as the initial enzyme in favonoid biosynthesis. The chalcone isomerase (CHI) enzyme further converts the intermediate molecule, naringenin in chalcone, into naringenin. In the next step of myricetin biosynthesis, the enzyme favone 3-hydroxylase (F3H) converts naringenin to pentahydroxyfavanone and dihydromyricetin. In the last stage of the biosynthesis of this compound, the favonol synthase (FLS), an enzyme, finally transformed the dihydromyricetin into myricetin.[3-4]

Chemical synthesis of myricetin

Kalf and Robinson's research groups synthesised myricetin from ω-methoxyphloroacetophenone in 1925. The first stage of this process involves heating the starting material with trimethylgallic anhydride and sodium trimethylgallate, following the product's hydrolysis results in the formation of an intermediate known as 5,7-dihydroxy-3,31,41,51-tetramethoxyfavone, and following the demethylation of the intermediate, which results in the formation of myricetin.[5]

Pharmacological action and Prospective application

Modern pharmacological studies showed that myricetin possesses a variety of biological activities such as anti-inflammatory, antitumor, antibacterial, antiviral, and anti-obesity effects, exerts cardiovascular protection, protects against neurological damage, and protects the liver against potential injuries.[1]

Multiple studies confirmed that myricetin possesses strong anti-cancer effects against various cancers (including colon, breast, prostate, bladder, and pancreatic cancers) through different mechanisms. Figure.2 shows some of the molecular mechanisms involved. Myricetin inhibits several proteins and signaling pathways promoting cell proliferation and inhibits apoptosis. Since it also induces cell cycle arrest, inhibits cell invasion and migration, and induces autophagy and necroptosis, it exerts a very good anti-tumor activity. At present, a large number of studies are available on the mechanism of myricetin regulating the antitumor activity in vitro, while more in vivo studies are needed to prove its clinical safety and confirm its effectiveness. More research is needed to understand its safety and efectiveness and address its potential limitations and drawbacks. Future research on myricetin for cancer treatment could concentrate on bioavailability enhancement, targeted delivery, clinical trials, combination therapy, and action mechanisms.

In addition to its anti-cancer effects, myricetin has strong anti-inflammatory activity and has a good protective effect on various inflammations such as mastitis, pneumonia, myocarditis and neuritis. Possible mechanisms involved include: regulation of receptor activator of nuclear factor-κB ligand (RANKL), regulation of toll-like receptor (TLR), inhibition of NF-κB-related signals induced by Lipopolysaccharide (LPS) and TNF-α and regulation of oxidative stress. Besides,MYR regulates the inflammatory response through the TNF-α signaling pathway. Generally, nephrotoxicity and colonic toxicity are dose limiting factors for cisplatin. MYR decreases the levels of inflammatory mediators (Nrf-2, TNF-α, NF-κB, COXI, COXII and IL-6), and reduces the levels of nephrotoxic markers (serum creatinine and blood urea nitrogen), to reduce inflammation and protect the kidney from inflammatory damage. More importantly, its cardiovascular, cerebrovascular and antineurodegenerative protective effect, and its resistance to pathogenic microorganism infection are closely related to its anti-inflammatory activity.[1] 

Furthermore, myricetin is an excellent immunomodulator, since it activates immune receptors and improves body immune function. Therefore, it can be used as an adjuvant treatment against cancer and nervous system diseases to improve the therapeutic effect of standard treatments.

Because of its strong anti-inflammatory effect, anti-myocardial damage, anti-viral activity, immune system regulation, oxidative stress reduction, and amelioration of cardiac dysfunction and arrhythmia, myricetin could also be a very promising compound against COVID-19, providing an effective treatment, although its effect and safety in the context of this disease is still poor and need further exploration.

References

[1] Song X, Tan L, Wang M, et al. Myricetin: A review of the most recent research. Biomed Pharmacother. 2021;134:111017.

[2] Kumar S, Swamy N, Tuli HS, et al. Myricetin: a potential plant-derived anticancer bioactive compound-an updated overview. Naunyn Schmiedebergs Arch Pharmacol. 2023;396(10):2179-2196.

[3] Javed Z, Khan K, Herrera-Bravo J, et al. Myricetin: targeting signaling networks in cancer and its implication in chemotherapy. Cancer Cell Int. 2022;22(1):239.

[4] Arafah A, Rehman MU, Ahmad A, et al. Myricetin (3,3',4',5,5',7-Hexahydroxyflavone) Prevents 5-Fluorouracil-Induced Cardiotoxicity. ACS Omega. 2022;7(5):4514-4524.

[5] Kalf J, Robinson R. XXVIII.—a synthesis of myricetin and of a galangin monomethyl ether occurring in galanga root. J Chem Soc Trans. 1925; 127:181–184.