Abstract
A series of novel 18βH-glycyrrhetinic acid (GA) derivatives containing 3′-(alkyl/phenyl/pyridin(-2″, -3″, and -4″)-yl)-1′,2′,4′-oxadiazole moieties at the C-30 position were synthesized by condensation of triterpenoid’s carboxyl group with corresponding amidoximes and further cyclization. Screening of the cytotoxicity of novel GA derivatives on a panel of tumor cell lines showed that the 3-acetoxy triterpenoid intermediates—O-acylated amidoxime 3a-h—display better solubility under bioassay conditions and more pronounced cytotoxicity compared to their 1′,2′,4′-oxadiazole analogs 4f-h (median IC50 = 7.0 and 49.7 µM, respectively). Subsequent replacement of the 3-acetoxy group by the hydroxyl group of pyridin(-2″, 3″, and -4″)-yl-1′,2′,4′-oxadiazole-bearing GA derivatives produced compounds 5f-h, showing the most pronounced selective toxicity toward tumor cells (median selectivity index (SI) > 12.1). Further detailed analysis of the antitumor activity of hit derivative 5f revealed its marked proapoptotic activity and inhibitory effects on clonogenicity and motility of HeLa cervical carcinoma cells in vitro, and the metastatic growth of B16 melanoma in vivo. Additionally, the comprehensive in silico study revealed intermediate 3d, bearing the tert-butyl moiety in O-acylated amidoxime, as a potent anti-inflammatory candidate, which was able to effectively inhibit inflammatory response induced by IFNγ in macrophages in vitro and carrageenan in murine models in vivo, probably by primary interactions with active sites of MMP9, neutrophil elastase, and thrombin. Taken together, our findings provide a basis for a better understanding of the structure–activity relationship of 1′,2′,4′-oxadiazole-containing triterpenoids and reveal two hit molecules with pronounced antitumor (5f) and anti-inflammatory (3d) activities.
Highlights
Oxadiazoles—five-membered ring heterocycles containing two carbon atoms, two nitrogen atoms, and one oxygen atom—are significant structural elements of organic compounds that are interesting in the fields of industrial materials [1,2,3,4] and biologically active substances [4,5]
We report the design, synthesis, and study of the spectrum of biological activities of novel 18βH-glycyrrhetinic acid (GA) derivatives containing alkyl/phenyl/pyridinyl1,2,4-oxadiazole rings instead of the native carboxylic group
It was shown that the addition of oxadiazole-containing moieties to triterpenoids markedly increased their cytotoxicity against tumor cells [24,25], enhanced selectivity for leukemia cells [69], and reinforced anti-inflammatory properties [70,71]
Summary
Oxadiazoles—five-membered ring heterocycles containing two carbon atoms, two nitrogen atoms, and one oxygen atom—are significant structural elements of organic compounds that are interesting in the fields of industrial materials [1,2,3,4] and biologically active substances [4,5]. Oxadiazole groups are important structural elements responsible for the emergence of new valuable properties in the obtained compounds. Oxadiazole derivatives, especially 1,2,4- and 1,3,4-regiostereoisomers, are widely represented in medical chemistry. These compounds have been shown to possess anti-inflammatory [6,7], antidiabetic [8], antibacterial [9], antituberculosis [10], and anticancer [11,12,13] activities, among others
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