Synthesis and evaluation of indole-containing 3,5-diarylisoxazoles as potential pro-apoptotic antitumour agents

A series of novel indole-containing diarylisoxazoles has been synthesised, based on our previous work on the synthesis and pro-apoptotic antitumour activity of indole-based diaryl 1,2,4-oxadiazoles. Concise synthetic routes to both 3-(indol-2-yl)-5-phenylisoxazoles and 5-(indol-2-yl)-3-phenylisoxazoles have been developed with full regiochemical control, bearing substituents on the indole ring, indole nitrogen, and/or phenyl group. Additionally a series of the related 5-(1H-indol-5-yl)-3-phenylisoxazoles has been prepared. In vitro evaluation in human cancer cell lines Colo320 (colon) and Calu-3 (lung) revealed preferential antiproliferative activity within the 5-(indol-5-yl)-3-phenylisoxazole series (low micromolar IC50). Further analysis revealed the ability of the indol-5-yl series to induce expression of effector caspases-3 and -7, and retention of viability of the human bronchial smooth muscle cell (BSMC) control cell population (particularly for compounds 18c and 18e).

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Regiospecific synthesis of indole-containing 3,5-diarylisoxazoles. ► Low micromolar (IC50) activity in Colo320 and Calu-3 human cancer cell lines. ► Most active pro-apoptotic compounds induce expression of effector caspases-3 and -7. ► Active compounds have little effect on normal bronchial smooth muscle cell line.