Sulfonamide derivatives of cis-imidazolines as potent p53-MDM2/MDMX protein-protein interaction inhibitors

Abstract

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 halogensubstituted 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.

Chlorosulfonic acid coated on porous organic polymer as a bifunctional catalyst for the one-pot three-component synthesis of 1,8-naphthyridines

“…These unique properties are due to the presence of nitrogen atoms in the carbon architecture of prepared support (PTBSA), which can be prepared easily from cheap nitrogen -rich precursors such as melamine. Because of these great features, nowadays, polysulfonamides is widely applied in different studies such as drug synthesis, 33 and heterogeneous catalyst. 20 In addition, PTBSA provide bifunctionality in the reaction mixture in the form of acid/base sites.…”

Application of In Silico Filtering and Isothermal Titration Calorimetry for the Discovery of Small Molecule Inhibitors of MDM2

“…Here we sampled the chemical groups on both sides of the central methanesulfonamide. Of note, compounds containing sulfonamide were recently reported as showing promising activity towards MDM2 [44]. M2-2 that has a benzene instead of the chlorobenzene, and M2-3 that has an additional 2-methyl on the indole, retained binding towards MDM2.…”

Utilizing Nitroarenes and HCHO to Directly Construct Functional N‐Heterocycles by Supported Cobalt/Amino Acid Relay Catalysis

“…N ‐aryl imidazolines constitute a class of highly important N‐heterocycles, and they have been found to exhibit diverse interesting biological and therapeutic activities [9, 10] . Moreover, they are useful precursors [11] for the preparation of N‐heterocyclic carbene (NHC) catalysts, [12–14] coordination ligands to transition metals, [15–18] and functional materials [19–21] .…”

“…N-aryl imidazolines constitute a class of highly important N-heterocycles, and they have been found to exhibit diverse interesting biological and therapeutic activities. [9,10] Moreover, they are useful precursors [11] for the preparation of Nheterocyclic carbene (NHC) catalysts, [12][13][14] coordination ligands to transition metals, [15][16][17][18] and functional materials. [19][20][21] In general, N-aryl imidazolines are synthesized by the condensation of N 1 ,N 2 -diarylethane-1,2-diamines (DAEDAs) with formaldehyde or its surrogates (Figure 1b).…”