TY - JOUR
T1 - Iminolactones as Tools for Inversion of the Absolute Configuration of alpha-Amino Acids and as Inhibitors of Cancer Cell Proliferation
AU - Jensen, Christina Mernøe
AU - Chow, Hsiao-Qing
AU - Chen, Ming
AU - Zhai, Lin
AU - Frydenvang, Karla Andrea
AU - Liu, Huizhen
AU - Franzyk, Henrik
AU - Christensen, Søren Brøgger
PY - 2016
Y1 - 2016
N2 - A library of iminolactones was prepared by esterification of several 2-hydroxyketones, of which some were of terpenoid origin while others were obtained via synthesis, with a number of N-protected D- and L--amino acids. After N-deprotection of the intermdiate 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--amino acids were partially epimerized at the -carbon atom to give a diasteromeric ester mixture. Only iminolactones of the L-amino acid were formed after cyclization of (1S,2S,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.
AB - A library of iminolactones was prepared by esterification of several 2-hydroxyketones, of which some were of terpenoid origin while others were obtained via synthesis, with a number of N-protected D- and L--amino acids. After N-deprotection of the intermdiate 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--amino acids were partially epimerized at the -carbon atom to give a diasteromeric ester mixture. Only iminolactones of the L-amino acid were formed after cyclization of (1S,2S,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.
KW - Former Faculty of Pharmaceutical Sciences
KW - Iminolactones, Inversion of amino acids, Anti-proliferative effects, Selective inhibition
U2 - 10.1016/j.ejmech.2016.02.037
DO - 10.1016/j.ejmech.2016.02.037
M3 - Journal article
C2 - 26974380
VL - 114
SP - 118
EP - 133
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
ER -