Rutin belongs to the flavonoid family and is widely found in traditional Chinese medicinal materials such as Huai Mi (the dried flower buds of Sophora japonica), Astragalus membranaceus, kudzu root, dried orange peel, and in fruits like lemons, oranges, cherries, grapes, apricots, plums, as well as vegetables such as asparagus, tomatoes, and cucumbers. Classified as Vitamin P, rutin can enhance the resilience of capillaries and regulate their permeability. It has functions in regulating blood lipids, preventing and treating cardiovascular and cerebrovascular diseases. Furthermore, it can be used as an active ingredient in pharmaceuticals, multivitamin preparations, cosmetics, the chemical industry, and animal feed.

Currently, the commonly used rutin products in China include Rutin Tablets, which are primarily utilized for fragile capillary hemorrhage, purpura, retinal hemorrhage, and other conditions; and Compound Rutin Tablets, whose main components are rutin and vitamin C, and are used in the treatment of cerebral hemorrhage, hemorrhagic nephritis, traumatic pulmonary hemorrhage, postpartum hemorrhage, and so forth. Although rutin has therapeutic effects on many diseases, its clinical application is somewhat limited due to its poor water solubility and low bioavailability.

Rutin is composed of three parts: quercetin, glucose, and rhamnose. Its structural formula is shown in the figure below, where AC represents the benzo(γ)pyran ring structure, the A ring is a resorcinol structure, the B ring contains a catechol structure, and the C ring is attached to a glucose moiety with three hydroxyl groups and a rhamnose moiety with three hydroxyl groups, meaning rutin contains four phenolic hydroxyl groups and six glycosidic hydroxyl groups.

To harness the preventive and therapeutic effects of rutin, researchers have optimized and modified its structure, primarily through modifications to the hydroxyl groups to form ethers and esters, modifications to the carbonyl group to generate substituted carbonyl oxygen products, and modifications to the quercetin A and B rings. Through these optimizations and modifications, rutin derivatives with improved solubility, higher bioavailability, and enhanced biological activities have been obtained.

1. Modification of Hydroxyl Groups

Hydroxyl groups are relatively reactive and can undergo a series of reactions. The modification of hydroxyl groups includes the modification of phenolic hydroxyl groups and glycosidic hydroxyl groups.

1.1 Modification of Phenolic Hydroxyl Groups

Derivatives resulting from the modification of phenolic hydroxyl groups include Troxerutin, rutin sulfonamide derivatives, rutin imidazole derivatives, rutin barbituric acid derivatives, rutin 6-aminopenicillanic acid derivatives, and rutin benzimidazole derivatives.

① Troxerutin, also known as Vinorutine, Vitamin P4, or Trihydroxyethylrutin, is a semi-synthetic flavonoid compound produced by hydroxyethylation of rutin. Troxerutin is widely used in the treatment of ischemic cerebrovascular diseases, such as those caused by chronic venous insufficiency, including cardiovascular and cerebrovascular diseases, chronic venous insufficiency, hemorrhoids, microvascular diseases, and retinopathy. Studies have found that Troxerutin also has a certain protective effect on cognitive impairments, namely diseases such as Alzheimer's disease and Parkinson's disease.

② Rutin sulfonamide derivatives. The widely used antibacterial sulfonamides have severe toxic and side effects on the kidneys, whereas rutin sulfonamide derivatives exhibit low toxicity and good water solubility. Among them, compounds with high activity include sulfapyridine and sulfachloropyridazine derivatives, which possess the same or even higher activity as cotrimoxazole. Both in vitro and in vivo antibacterial experiments of rutin sulfonamide derivatives have shown good antibacterial activity, with some compounds comparable to that of cotrimoxazole.

③ Rutin Imidazole Derivatives. When rutin, which is soluble in methanol, is treated with 1,3-dichloro-2-propanol and then reacted with imidazole or benzimidazole, respectively, the crude product is precipitated with isopropanol, filtered, eluted with 50% ethanol, and separated by silica gel column chromatography to obtain rutin imidazole derivatives. In vitro microbiological assays have shown that some of these derivatives exhibit good antifungal (Candida) activity and antibacterial (Gram-positive bacteria) effects.

④ Rutin Barbituric Acid Derivatives. Rutin is reacted with 1,3-dichloro-2-propanol in a methanol solution containing sodium methoxide, followed by a reaction with barbituric acid to obtain rutin barbituric acid derivatives. Data obtained after one month of animal experiments indicate that rutin barbituric acid derivatives can lower cholesterol and blood sugar levels, making them significant for the treatment of diabetes.

⑤ Rutin 6-Aminopenicillanic Acid Derivatives. Studies have shown that rutin possesses antibacterial properties and can also enhance the antibacterial activity of other compounds. While classical penicillin has low water solubility, rutin 6-aminopenicillanic acid derivatives are all water-soluble compounds that exhibit good antibacterial activity against both Gram-positive and Gram-negative bacteria, similar to ampicillin or chloramphenicol.

⑥ Rutin Benzimidazole Derivatives. Pyrimidine derivatives possess various pharmacological properties, including antiviral, antifungal, hypoglycemic, diuretic, and anticancer effects. By assessing the antioxidant activity of rutin and its derivatives using 1,1-diphenyl-2-picrylhydrazyl (DPPH) and comparing the results with natural and synthetic antioxidants, studies have found that rutin benzimidazole derivatives exhibit strong antioxidant activity in all tests. Some compounds possess the ability to scavenge free radicals and can be used as potent free radical inhibitors or scavengers.

1.2 Modification of Glycosidic Hydroxyl Groups

The modification of glycosidic bonds requires precise control over complex regioselectivity and stereoselectivity, often utilizing enzymatic synthesis methods. The enzymatic acylation reaction between rutin and fatty acids can improve the lipophilicity of rutin, enhancing its solubility and stability in lipophilic systems. The introduction of acyl groups can alter the membrane permeability, antioxidant, antibacterial, anti-inflammatory, antiproliferative, and enzyme inhibitory activities of rutin. Derivatives resulting from the modification of glycosidic hydroxyl groups include rutin acetate, rutin hexaacetate, rutin hexapropionate, rutin succinate, rutin dicarboxylic acid vinyl ester, rutin fatty acid esters, and rutin arachidonate.

① Rutin Acetate. Rutin acetate was synthesized through an enzymatic catalysis reaction, and the antioxidant, cytotoxic, and oxidative stress capabilities of the related products were evaluated. The results showed that rutin acetate was non-toxic to mammalian cells and effectively reduced reactive oxygen species in mouse macrophages. The insertion of the acyl group allowed for more effective high penetration into the cell membrane of mouse macrophages, reducing oxidative stress and enhancing stability in lipophilic media.

② Rutin Hexaacetate and Rutin Hexapropionate. The water solubility of rutin hexaacetate is approximately twice that of rutin, while its antioxidant activity is comparable. Rutin hexaacetate tablets exhibit better solubility than commercially available rutin tablets. Rutin hexapropionate displays antioxidant activity similar to rutin but exhibits superior antimicrobial activity, anti-inflammatory properties, and lipophilicity. It also possesses antiproliferative effects on human chronic myelogenous leukemia K562 cells. Experiments have shown that rutin hexapropionate can inhibit nuclear factor-kappa B (NF-κB) activity and promote apoptosis.

③ Rutin Succinate. By introducing a carboxylate ester group onto the glycosidic hydroxyl group of rutin, a water-soluble derivative known as rutin succinate can be synthesized. The solubility of rutin succinate in water increases by nearly 100 times, and its anti-free radical capacity is 1.5 times that of vitamin E. It can effectively inhibit lipid peroxidation in brain homogenate membranes and can be used as a free radical scavenger.

④ Rutin Dicarboxylic Acid Vinyl Ester. Synthesized through an enzymatically catalyzed regioselective reaction, rutin dicarboxylic acid vinyl ester can be used as a monomer for polymeric drugs or a precursor for functional materials. It also serves as a biosensing material, playing a significant role in drug delivery.

⑤Rutin Fatty Acid Esters. Experimental results indicate that the selective modification of rutin molecules with fatty acids can not only maintain the antioxidant capacity of rutin but also effectively increase its hydrophobicity and solubility in fats. As the number of carbon atoms in the fatty acid increases (from C12 to C18), the conversion rate of the ester gradually decreases. Rutin fatty acid esters play a crucial role in the prevention and treatment of diseases related to lipid peroxidation. The longer the fatty acid chain, the stronger the inhibitory effect of the corresponding rutin derivative on lipid peroxidation, with an average increase of 15%.

⑥ Rutin Arachidonate. Compared to rutin, selective acylation imparts effective antioxidant and anti-free radical properties, which are further enhanced in lipid/oil matrices. Enzyme inhibitory activity increases with acylation, likely due to enhanced membrane permeability and increased hydrophobicity. Rutin arachidonate can regulate the calcium signaling pathway through modulation of Ca2+-ATPase activity. Leveraging the lipophilic nature of fatty acids, rutin arachidonate can act as a serine protease inhibitor, particularly against thrombin.

2.Modification of Carbonyl Groups

Xanthine oxidase (XO) is a critical enzyme in purine metabolism, directly contributing to the development of gout and potentially contributing to cancer, diabetes, and metabolic syndrome. Inhibition of xanthine oxidase is an important approach in the treatment of gout, diabetes, and other metabolic syndromes. Enzyme kinetics studies have shown that the IC50 values of rutin Schiff base derivatives against xanthine oxidase (XO) range from 4.708 to 19.377 μmol/L. Molecular simulations reveal that the rutin Schiff base derivatives interact with the amino acid residue PHE798, located within the binding site of XO. Antioxidant activity assessments demonstrate that all derivatives exhibit excellent antioxidant capabilities. Molecular docking techniques indicate that rutin Schiff base derivatives function as inhibitors of xanthine oxidase.

3.Rutin Metal Complexes

Metal ions possess the remarkable ability to significantly alter the chemical properties of rutin. These ions can chelate with rutin to form metal complexes, which can be utilized as artificial metallonucleases or even as antitumor and antibacterial agents. Examples of rutin metal complexes include rutin zinc(II) complex, rutin-nickel(II) complex, rutin-copper(II) complex, rutin vanadium complex, and rutin alkali metal complexes.

Studies have shown that the rutin-zinc(II) complex exhibits no cytotoxicity towards normal cells (fibroblasts) and BALB/c mice, but possesses in vitro antioxidant and cytotoxic activities against leukemia KG1, K562, and Jurkat cells, multiple myeloma RPMI8226 cells, and melanoma B16F10 and SK-Mel-28 cells. The rutin-zinc(II) complex demonstrates higher antioxidant activity than free rutin, and its synergistic antitumor activity may help prevent the side effects of chemotherapy. The rutin-nickel(II) complex has higher free radical scavenging activity than free rutin, can moderately intercalate DNA, quench the strong intercalator ethidium bromide (EB), and compete for insertion binding sites. The potential antiproliferative effect of the rutin-copper(II) complex on human cervical adenocarcinoma HeLa cells was assessed using the conventional MTT assay. The rutin-copper(II) complex significantly inhibits the growth and proliferation of HeLa cells in a time- and dose-dependent manner. Experiments have shown that the rutin-vanadium complex enhances the antioxidant activity of the ligand against superoxide and hydroxyl radicals. Compared to rutin, the rutin-vanadium complex displays stronger anticancer activity and cellular reactive oxygen species (ROS) generation. It inhibits cell growth, leads to a significant increase in ROS formation, and decreases the glutathione (GSH)/oxidized glutathione (GSSG) ratio. These results suggest that the rutin-vanadium complex induces cell death through oxidative stress mechanisms, contributing to its anticancer effects. Rutin alkali metal complexes include complexes with lithium, sodium, potassium, rubidium, and cesium. Experiments on the antioxidant and antibacterial activities of rutin alkali metal complexes and rutin indicate that the rutin-rubidium complex exhibits the highest scavenging efficiency and strongest reducing power, while the rutin-sodium complex shows the highest activity against Pseudomonas aeruginosa and Bacillus subtilis after 48 hours of incubation.

References

[1] Li Ke, Feng Yali, Cao Ruimei, et al. Research Progress on Structural Modification and Biological Activities of Rutin [J]. Chinese Traditional and Herbal Drugs, 2021, 52(20): 6413-6424.

[2] Mao Yajun, Feng Yali, Wang Mengjiao, et al. Research Progress on Rutin Derivatives [J]. China Journal of Chinese Materia Medica, 2021, 46(18): 4654-4665.

About the Author

Xiaonisha, a food technology professional holding a Master's degree in Food Science, is currently employed at a prominent domestic pharmaceutical research and development company. Her primary focus lies in the development and research of nutritional foods, where she contributes her expertise and passion to create innovative products.