Novel Soloxolone Amides as Potent Anti-Glioblastoma Candidates: Design, Synthesis, In Silico Analysis and Biological Activities In Vitro and In Vivo | Sciact - CRIS-system of Boreskov Institute of Catalysis

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

Journal

Pharmaceuticals
ISSN: 1424-8247

Output data

Year: 2022, Volume: 15, Number: 5, Article number : 603, Pages count : 34 DOI: 10.3390/ph15050603

Tags

soloxolone methyl; amides; 18βH-glycyrrhetinic acid; bardoxolone methyl; glioblastoma; blood–brain barrier; antitumor activity; apoptosis; mitochondrial stress; tumor microenvironment

Authors

Markov Andrey V. ¹ , Ilyina Anna A. ^2,1 , Salomatina Oksana V. ^1,3 , Sen’kova Aleksandra V. ¹ , Okhina Alina A. ^2,3 , Rogachev Artem D. ^2,3 , Salakhutdinov Nariman F. ³ , Zenkova Marina A. ¹

Affiliations

1	Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
2	Faculty of Natural Sciences, Novosibirsk State University, 630090 Novosibirsk, Russia
3	N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia

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(24h) = 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.

Markov A.V. , Ilyina A.A. , Salomatina O.V. , Sen’kova A.V. , Okhina A.A. , Rogachev A.D. , Salakhutdinov N.F. , Zenkova M.A.
Novel Soloxolone Amides as Potent Anti-Glioblastoma Candidates: Design, Synthesis, In Silico Analysis and Biological Activities In Vitro and In Vivo
Pharmaceuticals. 2022. V.15. N5. 603 :1-34. DOI: 10.3390/ph15050603 WOS Scopus AN PMID OpenAlex

Submitted:	Apr 21, 2022
Accepted:	May 11, 2022
Published print:	May 14, 2022
Published online:	May 14, 2022

Web of science:	WOS:000801583700001
Scopus:	2-s2.0-85130729834
Chemical Abstracts:	2022:1435366
PMID:	35631429
OpenAlex:	W4280637872

DB	Citing
OpenAlex	9
Web of science	8
Scopus	8