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Amino acids as chiral derivatizing agents for antiproliferative substituted N‐benzyl isoindolinones
Author(s) -
Grigoreva Tatyana A.,
Novikova Daria S.,
Gureev Maxim A.,
Garabadzhiu Alexander V.,
Tribulovich Vyacheslav G.
Publication year - 2018
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/chir.22854
Subject(s) - diastereomer , chemistry , absolute configuration , stereochemistry , linker , amino acid , chiral auxiliary , combinatorial chemistry , organic chemistry , enantioselective synthesis , catalysis , biochemistry , computer science , operating system
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.