2,4,5-Tris(alkoxyaryl)imidazoline derivatives as potent scaffold for novel p53-MDM2 interaction inhibitors: Design, synthesis, and biological evaluation.

Abstract

Imidazoline-based small molecule inhibitors of p53-MDM2 interaction intended for the treatment of p53 wild-type tumors are the promising structures for design of anticancer drugs. Based on fragment approach we have investigated a key role of substituents in cis-imidazoline core for biological activity of nutlin family compounds. Although the necessity of the substituents in the phenyl rings of cis-imidazoline has been shown, there are no studies in which the replacements of a halogen by other substituents have been investigated. A series of simple cis-imidazoline derivatives containing halogen, hydroxy and alkoxy-substituents were synthesized. The biological activity of the compounds was studied using assays of cytotoxicity (MTT) and p53 level. It was found that the hydroxyl-derivatives were not cytotoxic whereas the alkoxy analogues were the same or more active as halogen-substituted compounds in cell viability test. The synthesized alkoxy derivatives induced an increase of p53 level and did not promote necrotic cell death in the concentration up to 40 µM.

• Authors: Daniil R Bazanov, Nikolay V Pervushin, Victoria Yu Savitskaya, Lada V Anikina, Marina V Proskurnina, Natalia A Lozinskaya, Gelina S Kopeina
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 29 Issue 16 Pg. 2364-2368 (08 15 2019) ISSN: 1464-3405 [Electronic] England
• PMID: 31196710 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Ltd. All rights reserved.

Chemical References

• Imidazolines
• Small Molecule Libraries
• Tumor Suppressor Protein p53
• MDM2 protein, human
• Proto-Oncogene Proteins c-mdm2

Topics

• A549 Cells
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Drug Design
• Humans
• Imidazolines (chemical synthesis, chemistry, pharmacology)
• Molecular Structure
• Protein Binding (drug effects)
• Proto-Oncogene Proteins c-mdm2 (antagonists & inhibitors, chemistry)
• Small Molecule Libraries (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship
• Tumor Suppressor Protein p53 (antagonists & inhibitors, chemistry)