Novel 3′-Substituted-1′,2′,4′-Oxadiazole Derivatives of 18βH-Glycyrrhetinic Acid and Their O-Acylated Amidoximes: Synthesis and Evaluation of Antitumor and Anti-Inflammatory Potential In Vitro and In Vivo

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.

Grafting of 18β-Glycyrrhetinic Acid and Sialic Acid onto Chitosan to Produce a New Amphipathic Chitosan Derivative: Synthesis, Characterization, and Cytotoxicity

“…However, GA is poorly soluble in water with low bioavailability, and long-term use can cause hyperaldosteronism: these factors limit its application greatly. To improve the activity of GA, the structure has been modified, and good results have been achieved [ 21 , 22 , 23 , 24 , 25 ]. Simultaneously, it has been found that GA can target hepatocyte membranes [ 26 ].…”

Novel Epoxides of Soloxolone Methyl: An Effect of the Formation of Oxirane Ring and Stereoisomerism on Cytotoxic Profile, Anti-Metastatic and Anti-Inflammatory Activities In Vitro and In Vivo

“…The lungs of the B16 melanoma-bearing mice were collected at the end of the experiment to calculate surface metastases using a binocular microscope. The inhibition of metastases development was assessed using the metastasis inhibition index (MII), calculated as described previously [ 59 ], where MII in the vehicle group was taken as 0% and MII reflecting the absence of metastases was taken as 100%.…”

A Novel 3-meta-Pyridine-1,2,4-oxadiazole Derivative of Glycyrrhetinic Acid as a Safe and Promising Candidate for Overcoming P-Glycoprotein-Mediated Multidrug Resistance in Tumor Cells

“…32 3-Acetoxy-18βH-glycyretinic acid (3) (purity ∼95%) was obtained by us as a result of acetic acid hydrolysis of the drug substance "Glycyram" (VFS 42-419-75, manufactured by JSC Chimpharm (Shymkent, Kazakhstan)) according to the previously published procedure. 44 The target compound 30-nor-3β-hydroxy-11-oxo-20-(3′-(pyridin-3″-yl)-1′,2′,4′-oxadiazol-5′-yl)-18βH-olean-12-en (2g) was obtained from 3-acetoxy-18βH-glycyretinic acid (3) according to the literature method 38 with a total yield of 64%. Details of the synthetic path, physicochemical characteristics, and NMR spectral information on the target compound 2g and its intermediates 1g and 4g are presented in Section S1 and Figures S3−S8.…”