A1 Journal article (refereed)
Activation of p53 signaling and regression of breast and prostate carcinoma cells by spirooxindole-benzimidazole small molecules (2024)

Barakat, A., Alshahrani, S., Al-Majid, A. M., Alamary, A. S., Haukka, M., Abu-Serie, M., Dömling, A., Domingo, L., & Elshaier, Y. A. M.M. (2024). Activation of p53 signaling and regression of breast and prostate carcinoma cells by spirooxindole-benzimidazole small molecules. Frontiers in Pharmacology, 15, Article 1358089. https://doi.org/10.3389/fphar.2024.1358089

JYU authors or editors

Publication details

All authors or editors: Barakat, Assem; Alshahrani, Saeed; Al-Majid, Abdullah Mohammed; Alamary, Abdullah Saleh; Haukka, Matti; Abu-Serie, Marwa, M.; Dömling, Alexander; Domingo, Luis, R.; Elshaier, Yaseen A. M. M.

Journal or series: Frontiers in Pharmacology

eISSN: 1663-9812

Publication year: 2024

Publication date: 08/04/2024

Volume: 15

Article number: 1358089

Publisher: Frontiers Media SA

Publication country: Switzerland

Publication language: English

DOI: https://doi.org/10.3389/fphar.2024.1358089

Publication open access: Openly available

Publication channel open access: Open Access channel

Publication is parallel published (JYX): https://jyx.jyu.fi/handle/123456789/94821

Publication is parallel published: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11033320/

Abstract

This study discusses the synthesis and use of a new library of spirooxindole-benzimidazole compounds as inhibitors of the signal transducer and activator of p53, a protein involved in regulating cell growth and cancer prevention. The text includes the scientific details of the [3 + 2] cycloaddition (32CA) reaction between azomethine ylide 7a and ethylene 3a within the framework of Molecular Electron Density Theory. The mechanism of the 32CA reaction proceeds through a two-stage one-step process, with emphasis on the highly asynchronous transition state structure. The anti-cancer properties of the synthesized compounds, particularly 6a and 6d, were evaluated. The inhibitory effects of these compounds on the growth of tumor cells (MDA-MB 231 and PC-3) were quantified using IC50 values. This study highlights activation of the p53 pathway by compounds 6a and 6d, leading to upregulation of p53 expression and downregulation of cyclin D and NF-kappa B in treated cells. Additionally, we explored the binding affinity of spirooxindole analogs, particularly compound 6d, to MDM2, a protein involved in regulation of p53. The binding mode and position of compound 6d were compared with those of a co-crystallized standard ligand, suggesting its potential as a lead compound for further preclinical research.

Keywords: heterocyclic compounds; bioactive compounds; inhibitors; carcinomas; breast cancer; prostate cancer; cancer cells; proteins; mutations; pharmaceutical chemistry; pharmacology

Free keywords: spirooxindole; benzimidazole; MEDT; p53; MDM2 inhibitors; NF-kappa B; CDK (cyclin-dependent kinase); electron dencity theory; induced apoptosis; mutant p53; inhibitors; participation; localization; exploration; design

Contributing organizations

Ministry reporting: Yes

VIRTA submission year: 2024

Preliminary JUFO rating: 1