Sulfonamide derivatives of cis-imidazolines as potent p53-MDM2/MDMX protein-protein interaction inhibitors
| Autor: | N. A. Lozinskaya, Egor V. Savin, Nikolay V. Pervushin, Anita I. Maksutova, Gelina S. Kopeina, Michael D. Tsymliakov, Daniil R. Bazanov, S. E. Sosonyuk |
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| Rok vydání: | 2021 |
| Předmět: |
chemistry.chemical_classification
MDMX medicine.diagnostic_test Organic Chemistry Substituent Imidazoline receptor Biological activity Combinatorial chemistry Sulfonamide chemistry.chemical_compound chemistry Western blot medicine Bioorganic chemistry General Pharmacology Toxicology and Pharmaceutics Solubility |
| Zdroj: | Medicinal Chemistry Research. 30:2216-2227 |
| ISSN: | 1554-8120 1054-2523 |
| Popis: | p53-MDM2/MDMX interaction inhibitors represent the prospective agents for targeted anticancer therapy in tumors expressing wild-type p53 protein. Imidazoline-based MDM2-targeted inhibitors of such type, nutlins, contain halogen-substituted phenyl rings, which dramatically decrease the solubility of compounds in water. The addition of suitable hydrophilic substituents in benzene rings and to imidazoline nitrogen can improve the compound’s water solubility. In this study, we have synthesized novel hydrophilic cis-2,4,5-tris(alkoxyphenyl)imidazolines and studied the influence of N-sulfonyl substituent on protein-protein interaction compared to unsubstituted alkoxy-compounds. The biological activity of the obtained compounds was studied using Western blot analysis on A549, RKO and SH-SY5Y cancer cell lines. It was found that the derivatives are able to inhibit MDM2/MDMX-p53 interaction, promote p53 stabilization and induce p21 expression in the concentrations from 500 nM. |
| Databáze: | OpenAIRE |
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