Novel Soloxolone Amides as Potent Anti-Glioblastoma Candidates: Design, Synthesis, In Silico Analysis and Biological Activities In Vitro and In Vivo

Abstract

The modification of natural or semisynthetic triterpenoids with amines can be explored as a promising strategy for improving their pharmacological properties. Here, we report the design and synthesis of 11 novel amide derivatives of soloxolone methyl (SM), a cyano enone-bearing derivative of 18βH-glycyrrhetinic acid. Analysis of their bioactivities in vitro and in silico revealed their high toxicity against a panel of tumor cells (average IC50(24 h) = 3.7 µM) and showed that the formation of amide moieties at the C-30 position of soloxolone did not enhance the cytotoxicity of derivatives toward tumor cells compared to SM, though it can impart an ability to pass across the blood–brain barrier. Further HPLC–MS/MS and mechanistic studies verified significant brain accumulation of hit compound 12 (soloxolone tryptamide) in a murine model and showed its high anti-glioblastoma potential. It was found that 12 induced ROS-dependent and autophagy-independent death of U87 and U118 glioblastoma cells via mitochondrial apoptosis and effectively blocked their clonogenicity, motility and capacity to form vessel-like structures. Further in vivo study demonstrated that intraperitoneal injection of 12 at a dosage of 20 mg/kg effectively inhibited the growth of U87 glioblastoma in a mouse xenograft model, reducing the proliferative potential of the tumor and leading to a depletion of collagen content and normalization of blood vessels in tumor tissue. The obtained results clearly demonstrate that 12 can be considered as a promising leading compound for drug development in glioblastoma treatment.

Soloxolone methyl induces apoptosis and oxidative/ER stress in breast cancer cells and target cancer stem cell population

“…Markov et al showed that U87 cells treated with NAC completely abolished the cytotoxic effect of the new soloxolon amides. This clearly shows that it is dependent on ROS ( Markov et al, 2022 ).…”

“…In a study with soloxolone amides, soloxolone tryptamide showed high antiproliferative potential in glioblastoma cells. Soloxolone tryptamide appeared to induce ROS-dependent and autophagy-independent death of U87 and U118 glioblastoma cells via mitochondrial apoptosis ( Markov et al, 2022 ). It has been demonstrated that 18p-glycyretinic acid causes HL60 cells to undergo apoptosis by increasing the generation of reactive oxygen species ( Makino et al, 2006 ).…”

Soloxolone Methyl Reduces the Stimulatory Effect of Leptin on the Aggressive Phenotype of Murine Neuro2a Neuroblastoma Cells via the MAPK/ERK1/2 Pathway

“…Previously, we showed that cyanoenone-bearing triterpenoid SM and its derivatives effectively inhibit the proliferation of KELLY and Neuro2a neuroblastoma cells at submicromolar concentrations [17] and exhibit an obvious suppressive effect on a range of metastasis-associated characteristics of tumor cells, such as EMT, motility, invasion, and clonogenicity [17,18,45]. Based on these facts, we decided to explore whether SM affects leptin-mediated processes in Neuro2a cells.…”

“…Previously, our research group developed soloxolone methyl (SM), a cyanoenonebearing semisynthetic derivative of glycyrrhetinic acid (Figure 1). This compound was shown to significantly inhibit the viability of NC-derived tumor cells [17] as well as the epithelial-mesenchymal transition (EMT) of melanoma B16 cells and their metastasis in vivo [18]. Considering the revealed antitumor potency of SM and the ability of 2-cyano-3, 12-dioxooleana-1, 9-dien-28-imidazolide (CDDO-Im) (a structural analog of SM; a semisynthetic derivative of oleanolic acid) to prevent body weight gain in high-fat diet-induced obese mice [19], the effect of SM and its analogs on adipokine-induced tumor cells is worthy of detailed investigation.…”

Halosulfonamidation of camphene: chemo and stereoselectivity, rearrangement, solvent interception, heterocyclization

“…Therefore, studies in the field of their synthesis, isolation, and antiviral properties have become especially important and timely. Terpene derivatives have been widely used as anticancer drugs, [3][4][5] antimicrobial agents, 6 anti-inflammatory drugs, 7 antiallergic medicines, 8 and antioxidants. 9 Bicyclic derivatives containing camphane, camphor, and pinane structures have demonstrated a wide range of antiviral activities.…”