However, plant cultures occupy a large area of cultivated land and plant growth may be affected by climate change and growth cycle, which subsequently reduces the adequate supply of raw materials. The challenges for UA’s application also do include current production methods which consume a lot of organic reagents, and eventually produce waste liquids to cause serious ecological pressure to surrounding environment. So the traditional extractions of UA make it difficult to meet the commercial needs and environmental protection goals.
Structure modification to improve the efficacy of UA
Although UA exhibits remarkable physiological and pharmacological activities with effective and safe therapeutic profile, its poor water solubility, short plasma half-life and poor bioavailability limit further clinical applications 44. In this regard, structural modifications of UA to cope with these limitations have been an attractive area of research to explore its valuable derivatives with enhanced pharmacological profile. In recent years, structural modification of UA is achieved by means of chemical transformation and microbial transformation to yield valuable derivatives.
4.1Chemical modification
UA structure is characterized by a hydroxyl group and carboxylic group which can be involved in the transfer of lone pair electrons to metal atoms 45. According to the structural properties of reported derivatives, UA usually undergoes structural modifications on C-3/C-28 positions or the ring A of UA skeleton.
4.1.1Modifications on C-3/C-28
Researchers isolated UA and five triterpenoids from apple peel and synthesized a series of UA analogs. Structural modification of UA at C-3 indicated significant anti-proliferative activity 46. In another study, acetyl group at the C-3 and an alkylamino and/or piperidine moiety at the C-28 enhanced the anticancer activity of UA derivative 46 (Fig. 2A ). In addition, structural modification of UA by addition of piperazine moieties may enhance its anti-cancer properties. Addition of acyl piperazine motif at C-28 position while C-3 retains the polar group significantly enhanced the anticancer activity against breast cancer and gastric cancer cell lines 47 (Fig. 2B ).
In order to clear on the mechanism of chemical modification at C-3 and C-28 in detail, researchers synthesized a series of UA derivatives by employing different electronic chemical modification at the two sites. Derivatives showed stronger cytotoxicity due to presence of positive charge (Fig. 2C ), indicating that the increased lipophilicity may enhance the therapeutic potential of gastric carcinoma48. These findings of UA derivatives led the ways to structurally modify the UA skeleton to yield its valuable derivatives with diverse pharmacological properties.