Research progress on structural modification and biological activity of dihydromyricetin
Dihydromyricetin (DHM, see Figure 1) is the main flavonoid component in Ampelopsis Grossedentata W. T. Wang, accounting for about 30% of its tender shoot dry weight. It has antioxidant, anti-inflammatory, antiviral, anticancer, antibacterial, anti fatigue, anti anxiety, hypoglycemic, hepatoprotective, cardioprotective, Alzheimer’s disease relieving, and asthma relieving effects.
DHM has good safety, and acute oral toxicity tests, long-term toxicity tests, and genotoxicity tests were conducted on rats and mice, all of which were negative. The stability of DHM is significantly weaker than other flavonoids because it has 6 hydroxyl groups, especially the hydroxyl group of the B ring, which is easily oxidized. PH ≥ 9, high temperature, and light exposure can accelerate DHM oxidation, greatly limiting its application. The solubility of DHM in water at 25 ℃ is 263.54mg/L, and heating can improve its water solubility. In a simulated digestive system, DHM exhibits pseudo first order kinetic degradation into non flavonoid compounds at a pH of 6.8. In addition, pH is considered the fundamental reason for the poor stability of DHM in the gastrointestinal tract, leading to its poor bioavailability. In order to enhance its anti-tumor, antibacterial, antiviral, anti-inflammatory, antioxidant, and neuroprotective activities, researchers have conducted extensive experimental studies on DHM and achieved certain research results. This article provides a review from the aspects of structural modification and biological activity, and points out the problems and development directions in the structural modification process of dihydromyricetin, providing technical services for better development of dihydromyricetin derivatives.

The successful structural modification of natural products needs to be evaluated from the aspects of synthetic feasibility, biological activity and physical and chemical properties. For example, the introduction of a methyl group into the structure of DHM can significantly inhibit COVID-19. In the future structural modification process, the modification sites can focus on: ① modification on the A ring of dihydromyricetin, using Friedel Crafts or Mannich reactions to introduce different groups at C-6 or 8 positions, and then splicing with existing drugs to form twin drugs; ② Classic modification methods can be used to carry out etherification or esterification reactions on different hydroxyl groups, but special attention should be paid to the conformational changes of the modified products It is also possible to involve unexplored modifications only to DHM 5-OH while retaining other hydroxyl groups, in order to discover new biological activities. Difficulties in DHM structural modification: ① It is often difficult to achieve the specified hydroxyl protection or deprotection in the protection and deprotection reactions; ② During the reaction and separation purification process, DHM is prone to oxidation to myricetin or conversion to chalcone, resulting in complex and difficult to separate products. The diverse pharmacological activities of DHM have attracted numerous researchers to enhance their pharmacological activities and understand their potential pharmacological groups through chemical modifications. DHM derivatives will undoubtedly bring new hope to the development of new drugs.