New synthetic analogues of natural 5Z,9Z-dienoic acids: Stereoselective synthesis and study of the anticancer activity.

ABSTRACT

A stereoselective method was developed for the synthesis of synthetic analogues of natural 5Z,9Z-dienoic acids by esterification of aliphatic and aromatic alcohols and carboxylic acids with (5Z,9Z)-1,14-tetradeca-5,9-dienedioic acid and (5Z,9Z)-1,14-tetradeca-5,9-dienediol, synthesized by Ti-catalyzed homo-cyclomagnesiation of the tetrahydropyran ether of hepta-5,6-dien-1-ol with Grignard reagents. In order to establish the effect of molecular structure on the antitumor activity, the obtained 5Z,9Z-dienoic acids were tested for the inhibitory activity against human topoisomerase I, the cytotoxic activity in vitro against several cancer and normal cell lines (Jurkat, HL-60, K562, U937, fibroblasts), the effect on the cell cycle, and apoptosis-inducing ability using flow cytofluorometry. In addition, the effect of the synthesized acids on the cancer cell production of some phosphorylated and unphosphorylated proteins responsible for proliferation and apoptosis was studied by a new multiplex assay technology, MAGPIX.