Iminolactones as tools for inversion of the absolute configuration of α-amino acids and as inhibitors of cancer cell proliferation

A library of iminolactones was prepared by esterification of several 2-hydroxyketones with a number of N-protected D- and L-alpha-amino acids. Some of the hydroxyketones were of terpenoid origin while others were obtained via synthesis. After N-deprotection of the intermediate esters, the free amines spontaneously underwent condensation with the ketone to form iminolactones. Esters of (1S,2S,5S)-2-hydroxypinan-3-one with both D- and L-alpha-amino acids were partially epimerized at the alpha-carbon atom to give a diastereomeric ester mixture. Only iminolactones of L-amino acids were formed after cyclization of (1S,25,5S)-2-hydroxypinan-3-one, and correspondingly only D-amino acid iminolactones were formed after reaction with (1R,2R,5R)-2-hydroxypinan-3-one. The protocol thus enables inversion of the absolute configuration of amino acids. Some members of the prepared library of iminolactones displayed significant anti-proliferative effects toward three cancer cell lines (EL4, MCF7, PC3) with insignificant effect on non-malign cell lines (McCoy, MCF10A, NIH3T3). Thus, iminolactones appear to be potential lead structures for preparation of drugs selectively affecting proliferation of malign cell lines. (C) 2016 Elsevier Masson SAS. All rights reserved.