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Phloretin (C15H14O5, CAS No. 60-82-2), chemical name: 2,4,6-Trihydroxy-3-(4-hydroxyphenyl)acetophenone, is a pearly white crystalline powder that is soluble in alkaline solutions and easily soluble in methanol, ethanol, and acetone, but almost insoluble in water. Other names for Phloretin include Phloroglucinol Acetone, and it belongs to the flavonoid class of compounds. It is primarily found in various plants such as the branches, leaves, fruits/skins, and roots/peels of apple trees, as well as the skins of lychee fruits, Tibetan medicinal plant “Ose leaves,” and other species like multi-spike tea and crabapple. Phloretin can be directly absorbed by the human body. However, in plants, Phloretin is rarely found in its free form and mostly exists as its glycoside derivative—phloridzin. Once absorbed by the human body, phloridzin is hydrolyzed by the gastric mucosa to form Phloretin, which can then enter the bloodstream and exert its effects. Phloretin has various pharmacological activities, including antioxidant, anti-tumor, anti-inflammatory, immunosuppressive, and bone-forming promotion effects. Additionally, it has cosmetic properties such as skin whitening and acne treatment. It can be used in facial masks, skincare creams, lotions, and serums. Furthermore, Phloretin is also an effective inhibitor of sodium-dependent glucose transporters (SGLT) 1 and 2, and glucose transporter proteins (GLUT) 1 and 2. Phloretin has diverse physiological functions. In the pharmaceutical field, it is used as a natural agent for lowering blood sugar, cardiovascular protection, and cancer treatment. In the cosmetics industry, Phloretin is effective in treating acne caused by Staphylococcus aureus and Propionibacterium acnes infections. It is also used to inhibit tyrosinase activity, preventing melanin formation and providing whitening effects, making it a novel natural whitening agent for cosmetics. Phloretin’s potent antioxidant properties make it useful in anti-aging skincare products. In the food industry, Phloretin is permitted as a flavor additive with no specific dosage restrictions. Due to its strong antioxidant and antimicrobial activities, it can also be developed as a natural preservative. Moreover, with its numerous beneficial physiological functions and safety, there is potential for the development of functional foods containing Phloretin. Currently, Phloretin and its glycoside products are primarily extracted and isolated from plants. However, they are often present alongside other flavonoids such as naringin, flavanones, flavanols, and other flavonoid derivatives, which complicates the extraction and purification process. As a result, large-scale, high-purity preparation of Phloretin remains challenging. In recent years, with the rapid development of metabolic engineering and synthetic biology technologies, microbial metabolic engineering has become a research focus. The construction of microbial "cell factories" to synthesize natural products has gained significant attention. Methods of Phloretin Preparation: 1. Extraction and Isolation from Natural Products 1.1 Extraction from Apple Trees and Fruits In 1835, French chemists first isolated phloridzin from apple tree bark, and later discovered that Phloretin and phloridzin were abundant in various parts of the apple tree, including bark, stems, leaves, and fruits. Phloridzin can be extracted from apple tree bark using organic solvents (e.g., methanol, ethanol), and separated and purified by high-efficiency liquid chromatography. Hydrolysis with acid (e.g., hydrochloric acid or sulfuric acid) can then yield Phloretin. The content of phloridzin varies across different parts of the apple tree, with the highest concentration found in the bark (64.32 mg/g), followed by the leaves (40.30 mg/g) and branches (30.43 mg/g). Phloridzin has been extracted from apple fruit drops (young fruits), with a yield of 0.104% and a purity of 97.52%. The dynamic content of phloridzin in apple trees varies seasonally, with the highest content in the leaves in September and October (16.31 mg/g), and the highest content in the branches in June (11.93 mg/g). Phloretin was only detected in the leaves, with the highest concentration in May (2.541 mg/g). It has also been found that apple variety influences the Phloretin content. Using high-performance liquid chromatography-diode array detection (HPLC-DAD), the phenolic compound content in various apple varieties was measured. The Phloretin content in the peels ranged from 61 to 122 mg/kg in red apples, 29 to 31 mg/kg in green apples, and 58 to 71 mg/kg in golden apples. In the flesh, the Phloretin content ranged from 2 to 4 mg/kg in red apples, 7.00 mg/kg in green apples, and 5 to 8 mg/kg in golden apples. 1.2 Extraction from Other Plants Recently, Phloretin and phloridzin have been extracted from other plants as well. For example, multi-spike tea has been extracted using microwave-assisted Ca(OH)2 aqueous solution, yielding a flavonoid content of 40%, with phloridzin accounting for 29.5%. Phloridzin has also been identified in lychee fruit peel, which can be extracted using ethanol solvent in ultrasonic extraction or hot reflux methods. 1.3 Extraction from Tibetan Medicine “Ose Leaves” Phloretin and phloridzin have also been isolated from Ose leaves (species of Malus, rose family). The average content of phloridzin in Ose leaves is 22.11%, and the average Phloretin content is 0.51%. Ultrasound-assisted methanol extraction of the leaves, stems, and fruits of various species of Malus yielded different phloridzin content, with values such as 12.00 ± 3.60 mg/g for leaves, 21.60 ± 6.10 mg/g for stems, and 1.18 ± 0.15 mg/g for fruits. Phloridzin is also found in other species like the wild pear (Pyrus), rose family plants, and other botanical sources, indicating its wide distribution in nature. 2. Chemical Synthesis of Phloretin Due to the low content of Phloretin in natural plants and the high extraction costs, researchers have attempted chemical synthesis for semi-synthesis and total synthesis of Phloretin. 2.1 Semi-synthesis Phloretin can be prepared by hydrolyzing phloridzin using acid (usually hydrochloric acid or sulfuric acid) or enzymatic hydrolysis with glucosidase. For example, naringin can be used as a raw material to synthesize Phloretin via hydrogenation and acidic hydrolysis. 2.2 Total Synthesis Phloretin can be synthesized using raw materials such as 2'-hydroxy-4',6'-dimethoxyphenylacetone and p-methoxyphenylacetaldehyde. Through a series of reactions, including aldol condensation and catalytic hydrogenation, Phloretin can be synthesized with a high degree of purity. Other methods involve the use of esters or acylation reactions to form intermediate compounds, followed by Fries rearrangement to yield Phloretin. 3. Biological Synthesis of Phloretin Compared to other synthetic methods, biological synthesis of Phloretin and phloridzin is less reported. Researchers have used recombinant enzymes and plant protein extracts to study the biosynthesis of Phloretin and phloridzin. In apple plants, the two precursor substances involved in the biosynthesis of Phloretin are malonyl-CoA and p-coumaroyl-CoA. The biosynthesis pathway involves chalcone synthase and other enzymes, ultimately leading to the production of Phloretin. Some genes, such as ENRL-3 and ENRL-5, are believed to play a crucial role in the biosynthesis of phloridzin. Currently, the main methods for Phloretin preparation are based on natural product extraction combined with chemical synthesis. Biological synthesis has not yet reached commercialization.
