TY - JOUR

T1 - Novel Soloxolone Amides as Potent Anti-Glioblastoma Candidates: Design, Synthesis, In Silico Analysis and Biological Activities In Vitro and In Vivo

AU - Markov, Andrey V.

AU - Ilyina, Anna A.

AU - Salomatina, Oksana V.

AU - Sen’kova, Aleksandra V.

AU - Okhina, Alina A.

AU - Rogachev, Artem D.

AU - Salakhutdinov, Nariman F.

AU - Zenkova, Marina A.

N1 - Funding Information: Funding: This work was funded by the Russian Science Foundation, grant number 17-75-20120, (synthesis, in vitro, in silico and in vivo studies) and funded by the Russian State-funded budget project of ICBFM SB RAS, grant number 121031300044-5 (in the development of basic methods). Publisher Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2022/5

Y1 - 2022/5

N2 - 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 ac-cumulation 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 autopha-gy-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.

AB - 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 ac-cumulation 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 autopha-gy-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.

KW - 18βH-glycyrrhetinic acid

KW - amides

KW - antitumor activity

KW - apoptosis

KW - bardoxolone methyl

KW - blood–brain barrier

KW - glioblas-toma

KW - mitochondrial stress

KW - soloxolone methyl

KW - tumor microenvi-ronment

UR - http://www.scopus.com/inward/record.url?scp=85130729834&partnerID=8YFLogxK

UR - https://www.mendeley.com/catalogue/04f53683-1db7-3350-8651-a904a96d56e1/

U2 - 10.3390/ph15050603

DO - 10.3390/ph15050603

M3 - Article

C2 - 35631429

AN - SCOPUS:85130729834

VL - 15

JO - Pharmaceuticals

JF - Pharmaceuticals

SN - 1424-8247

IS - 5

M1 - 603

ER -