Synthesis of Novel Heterocyclic Ring‐Fused 18β‐Glycyrrhetinic Acid Derivatives with Antitumor and Antimetastatic Activity

Abstract

Glycyrrhetinic acid (GA) is one of the most important triterpenoic acids shows many pharmacological effects, especially antitumor activity. GA triggers apoptosis in various tumor cell lines. However, the antitumor activity of GA is weak, thus the synthesis of new synthetic analogs with enhanced potency is needed. By introducing various five-member fused heterocyclic rings at C-2 and C-3 positions, 18 novel GA derivatives were obtained. These compounds were evaluated for their inhibitory activity against the growth of eight different tumor cell lines using a SRB assay. The most active compound 37 showed IC50 between 5.19 and 11.72 μm, which was about 11-fold more potent than the lead compound GA. An apoptotic effect of GA and 37 was determined using flow cytometry and trypan blue exclusion assays. We also demonstrated here for the first time that GA and the synthetic derivatives exhibited inhibitory effect on migration of the tested tumor cells, especially 37 which was about 20-fold more potent than GA on antimetastatic activity.

The Protective Effects of 18β-Glycyrrhetinic Acid on Imiquimod-Induced Psoriasis in Mice via Suppression of mTOR/STAT3 Signaling

“…18 β -Glycyrrhetinic acid (GA, structure shown in Figure 1 ), an aglycone and active metabolite of glycyrrhizic acid, has been shown to have a series of pharmacological effects such as antioxidative [ 12 , 13 ], antitumor [ 14 – 16 ], and anti-inflammatory [ 17 , 18 ] activities. Moreover, in recent years, this compound has also been reported to show some protective effect in skin disorders [ 19 – 21 ].…”

Pentacyclic triterpenoids with nitrogen- and sulfur-containing heterocycles: synthesis and medicinal significance

“…However, there are many other reasons why cancer is so prevalent. Finally, heterocyclic derivatives are easily prepared in selectively-labeled form, due to the good availability of building blocks in isotopic form ( 15 N, 33 S, etc.). In conjunction with this lack of success in current therapy it is important that optional treatment possibilities of this insidious and dangerous disease are still being explored.…”

Synthesis and Cytotoxic Activity of Triterpenoid Thiazoles Derived from Allobetulin, Methyl Betulonate, Methyl Oleanonate, and Oleanonic Acid

“…[13] Recently,m any cytotoxic derivatives were found among triterpenes that contain ah eterocycle fused to the A-ring of the triterpenoid skeleton. The mosta ctive compounds were indoles, [14,15] pyrazoles, [14,[16][17][18][19][20][21][22] isoxazoles, [23,24] triazoles, [25] pyrazines, [14,20,[26][27][28][29][30] quinoxalines, [14] pyrimidines, [23] and triazines. [31,32] Previously,w es ynthesized as et of triterpenes modified with five membered heterocycles and among them aminothiazole derivative 1 was the most active on multiple cancer cell lines, [19] which sparked our interest in such compounds.…”