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Letters in Drug Design & Discovery

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ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

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Research Article

Aryl-isoquinoline as a Potential Scaffold for Novel Antitumor Agents against Glioblastoma Cells

Author(s): Thais Batista Fernandes, Rosania Yang, Glaucio Monteiro Ferreira, Priscila Oliveira de Souza, Vitor Galvão Lopes, Mônica Franco Zannini Junqueira Toledo, Gabriela Gonçalves Roliano, Gabriela Nogueira Debom, Sandra Valeria Vassiliades, Neuza Mariko Aymoto Hassimotto, Mario Hiroyuki Hirata, Elizandra Braganhol and Roberto Parise-Filho*

Volume 21, Issue 5, 2024

Published on: 22 February, 2023

Page: [948 - 960] Pages: 13

DOI: 10.2174/1570180820666230131111033

Price: $65

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Abstract

Background: Glioblastoma is one of the most aggressive types of tumors, which occurs in the central nervous system, and has a high fatality rate. Among the cellular changes observed in glioblastoma is the overexpression of certain anti-apoptotic proteins, such as Bcl-xL. Recently, the alkaloid sanguinarine (SAN) was identified as a potent inhibitor of this class of proteins.

Objective: In this work, the antitumor activity of ten aryl-isoquinolines that were synthesized based on molecular simplification of SAN was investigated.

Methods: The SAN derivatives were prepared by Suzuki reaction and bimolecular nucleophilic substitution. The compounds were tested against glioblastoma (U87MG) and melanoma (A375) tumor lines in the MTT and SRB assay. The cell death mechanism was evaluated by flow cytometry. The molecular modeling study was used to evaluate the interactions between the prepared compounds and the Bcl-xL protein.

Results: Analogues presented IC50 values against glioblastoma lower than temozolomide. Evaluation against astrocytes and fibroblasts indicated that the analogues were significantly superior to SAN regarding selectivity. The most active compound, 2e, induced phosphatidylserine externalization and mitochondrial membrane depolarization, indicating apoptotic death by the intrinsic pathway. In addition, 2e provides cell cycle arrest at the G2/M phase. Molecular dynamics suggested that 2e interacts with Bcl-xL mainly by hydrophobic interactions.

Conclusion: In our study, aryl-isoquinoline represents a relevant scaffold to be explored by medicinal chemists to develop potential anti-glioblastoma agents.

Keywords: Glioma, tumor brain, Bcl-xL, sanguinarine, aryl-isoquinoline, molecular simplification, cytotoxicity, molecular dynamics.

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