Novel Soloxolone Amides as Potent Anti-Glioblastoma Candidates: Design, Synthesis, In Silico Analysis and Biological Activities In Vitro and In Vivo
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 (<b>SM</b>), a cyano enone-bearing de...
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| Main Authors: | , , , , , , , |
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| Format: | Book |
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MDPI AG,
2022-05-01T00:00:00Z.
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| Online Access: | Connect to this object online. |
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| Summary: | 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 (<b>SM</b>), 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 IC<sub>50</sub><sup>(24h)</sup> = 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 <b>SM</b>, 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 <b>12</b> (soloxolone tryptamide) in a murine model and showed its high anti-glioblastoma potential. It was found that <b>12</b> 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 <b>12</b> 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 <b>12</b> can be considered as a promising leading compound for drug development in glioblastoma treatment. |
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| Item Description: | 10.3390/ph15050603 1424-8247 |