Amino acids as chiral derivatizing agents for antiproliferative substituted N‐benzyl isoindolinones

Abstract

The absolute configurations of the diastereomers of novel amino acid ester derivatives of 2,3-substituted isoindolinones, which are known as apoptosis activators due to their ability to inhibit the MDM2-p53 PPI, were assigned using NMR and computational methods. Procedures for diastereomer separation and determining the absolute configuration were developed to perform the study. The high significance of N-benzyl fragment for the determination of the diastereomer absolute configuration by NMR methods was established; it is determined by a number of factors inherent in this fragment and the structural features of the studied substrates. Analysis of the individual isomer activity showed that the target inhibitory effect of S- and R-isoindolinone L-valinates differs by less than 20%. It can be explained by the presence of a flexible linker between the isoindolinone core and amino acid fragment, which provides the optimal arrangement of the molecule in the hydrophobic cavity of MDM2 for both isomers.

Treatment of chemoresistant cell lines with indolinone-based small molecules

“…We showed that indolinone derivatives can effectively induce apoptosis of cancer cells by the example of U2OS (human osteosarcoma) and HEK293T (human embryonic kidney) cell lines with different p53 status, at the same time the mechanism of the drugs was confirmed using recombinant protein models of p53 and MDM2 [9,12,18]. On the other hand, substances based on the indolinone scaffold confirmed their effectiveness in preventing and/or slowing down the development of multidrug resistance; promising results were obtained not only in experiments in cells, but also in xenografts [22,23].…”

“…The library was based on classes of compounds studied in our laboratory, which in in vitro experiments showed activity comparable to the activity of substances at the stage of clinical trials [18,19] (Fig. 1).…”

The First Highly Enantioselective Synthesis of 3-Sulfinyl-Substituted Isoindolinones Having Adjacent Carbon and Sulfur Stereocenters

“…In fact, calculations for (C S* ,S S* )-4d stable conformers indicate that the above-mentioned nuclei experience a significantly different magnetic environment which would result in a downfield shift of their resonances both in 1 H and 13 C NMR spectrum (see Table S1 for details). 12…”

Analysis of P-Glycoprotein Transport Cycle Reveals a New Way to Identify Efflux Inhibitors

“…It should be noted that in the case of rigid targets, such as Mdm2 − or AMPK, − docking clearly proves its effectiveness and high predictive power. However, the structure of P-gp has a number of fundamental differences.…”