Aminoanalogues of isobrassinin, erucalexin and isocyclobrassinin: Synthesis and evaluation of the antiproliferative and cytotoxic properties

Abstract

This work deals with a synthetic effort to obtain regioisomeric amino analogues of the natural indole phytoalexins brassinin, 1-methoxyspirobrassinin and cyclobrassinin. In order to improve the antiproliferative effect, our attention was focused on bioisosteric and regioisomeric optimization of the structure of indole phytoalexins. Starting from 1-substituted (indol-2-yl) methylamine derivatives, thioureas were prepared and then transformed by oxidative spirocyclization with chromium dioxide, Hugerschoff ring-closure or methyl bromoacetate. The twenty-three novel compounds were evaluated for in vitro antiproliferative activity against human cancer cell lines. Compounds 20 and 27 were shown to be potent antiproliferative agents with IC50 values in the low micromolar range. Compounds 20 and 27 exhibited better antiproliferative/cytotoxic effect against Jurkat, MCF-7 and HCT116 cells (IC50 < 10 μM) than cisplatin. This work revealed that efficacy against cancer cell lines does not improve depending on the regioisomeric position.