An Overview of Structurally Modified Glycyrrhetinic Acid Derivatives as Antitumor Agents

Abstract

Glycyrrhetinic Acid (GA), a triterpenoid aglycone component of the natural product glycyrrhizinic acid, was found to possess remarkable anti-proliferative and apoptosis-inducing activity in various cancer cell lines. Though GA was not as active as other triterpenes, such as betulinic acid and oleanolic acid, it could trigger apoptosis in tumor cells and it can be obtained easily and cheaply, which has stimulated scientific interest in using GA as a scaffold to synthesize new antitumor agents. The structural modifications of GA reported in recent decades can be divided into four groups, which include structural modifications on ring-A, ring-C, ring-E and multiple ring modifications. The lack of a comprehensive and recent review on this topic prompted us to gather more new information. This overview is dedicated to summarizing and updating the structural modification of GA to improve its antitumor activity published between 2005 and 2016. We reviewed a total of 210 GA derivatives that we encountered and compiled the most active GA derivatives along with their activity profile in different series. Furthermore, the structure activity relationships of these derivatives are briefly discussed. The included information is expected to be of benefit to further studies of structural modifications of GA to enhance its antitumor activity.

18ß-glycyrrhetinic acid derivative promotes proliferation, migration and aquaporin-3 expression in human dermal fibroblasts

“…So far, most GA-ds have been synthesized based on the structure of 18β-GA, rather than that of the 18α stereo-isomeric form. The structural or chemical modifications of 18β-GA usually focus on the functional groups of ring A, C, E, or multiple rings [ 7 , 8 ]. Many 18β-GA-ds show prominent cytotoxic activity [ 7 , 33 , 34 ], and most cytotoxic 18β-GA-ds showed optimum cytotoxicity at concentrations less than 30 μM [ 7 ].…”

“…Thus, many derivatives of 18β-GA have been synthesized, based on its structure [ 7 ]. Most of these derivatives are cytotoxic, and have been evaluated for possible anti-tumor properties [ 8 ]. Some 18β-GA derivatives have served as anti-inflammatory and antioxidant agents [ 9 ].…”

Efficient synthesis of piperazinyl amides of 18β-glycyrrhetinic acid

“…Over the past few decades, the emphasis was placed primarily on explaining structure-activity relationships of 18β-glycyrrhetinic acid derivatives to enhance their biological activity. The structure of 18β-glycyrrhetinic acid offered numerous possibilities to chemical modifications, thereby leading to the formation of novel derivatives [7][8][9]. There are three functional groups at C-3, C-11 and C-30 in the structure of 18β-glycyrrhetinic acid amenable to chemical modifications.…”

“…The modifications at the C3-OH group of 18β-glycyrrhetinic acid are identified to be relatively common and effective. The modification of the C3-OH group, altering the molecular polarity of 18β-glycyrrhetinic acid, may be an advantage in achieving better cytotoxicity or antiproliferative activity [8][9][10]. For instance, the hydroxy group can be converted into an oxime, acyloxyimino, alkoxyimino, alkoxy and 3-oxo group [9].…”

“…The modification of the C3-OH group, altering the molecular polarity of 18β-glycyrrhetinic acid, may be an advantage in achieving better cytotoxicity or antiproliferative activity [8][9][10]. For instance, the hydroxy group can be converted into an oxime, acyloxyimino, alkoxyimino, alkoxy and 3-oxo group [9]. As a proteasome inhibitor, compound a suppresses the chymotrypsin-like activity of the proteasome in MT4 cells with an IC 50 of 0.22 μM, nearly 100-fold more potent than 18βglycyrrhetinic acid.…”