Rapid Access to Ironomycin Derivatives by Click Chemistry

Michał Antoszczak; Sebastian Müller; Ludovic Colombeau; Tatiana Cañeque; Raphaël Rodriguez

doi:10.1021/acsorginorgau.1c00045

Rapid Access to Ironomycin Derivatives by Click Chemistry

ACS Org Inorg Au. 2022 Jun 1;2(3):222-228. doi: 10.1021/acsorginorgau.1c00045. Epub 2022 Jan 21.

Authors

Michał Antoszczak^{1

2}, Sebastian Müller¹, Ludovic Colombeau¹, Tatiana Cañeque¹, Raphaël Rodriguez¹

Affiliations

¹ Department of Chemical Biology Institut Curie, CNRS UMR 3666, INSERM U1143, PSL Université 26 rue d'Ulm, 75005 Paris, France.
² Department of Medical Chemistry Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61-614 Poznań, Poland.

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 CD24^low/CD44^high) and its corresponding epithelial counterpart (HMLER CD24^high/CD44^low) 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.