Rapid Access to Ironomycin Derivatives by Click Chemistry

Abstract

Salinomycin, a natural carboxylic polyether ionophore, shows a very interesting spectrum of biological activities, including selective toxicity toward cancer stem cells (CSCs). Recently, we have developed a C20-propargylamine derivative of salinomycin (ironomycin) that exhibits more potent activity in vivo and greater selectivity against breast CSCs compared to the parent natural product. Since ironomycin contains a terminal alkyne motif, it stands out as being an ideal candidate for further functionalization. Using copper-catalyzed azide-alkyne cycloaddition (CuAAC), we synthesized a series of 1,2,3-triazole analogs of ironomycin in good overall yields. The in vitro screening of these derivatives against a well-established model of breast CSCs (HMLER CD24low/CD44high) and its corresponding epithelial counterpart (HMLER CD24high/CD44low) revealed four new products characterized by higher potency and improved selectivity toward CSCs compared to the reference compound ironomycin. The present study highlights the therapeutic potential of a new class of semisynthetic salinomycin derivatives for targeting selectively the CSC niche and highlights ironomycin as a promising starting material for the development of new anticancer drug candidates.