Expeditive Synthesis of Potent C20- epi-Amino Derivatives of Salinomycin against Cancer Stem-Like Cells

Dominika Czerwonka; Sebastian Müller; Tatiana Cañeque; Ludovic Colombeau; Adam Huczyński; Michał Antoszczak; Raphaël Rodriguez

doi:10.1021/acsorginorgau.1c00046

Expeditive Synthesis of Potent C20- epi-Amino Derivatives of Salinomycin against Cancer Stem-Like Cells

ACS Org Inorg Au. 2022 Jun 1;2(3):214-221. doi: 10.1021/acsorginorgau.1c00046. Epub 2022 Jan 5.

Authors

Dominika Czerwonka^{1

2}, Sebastian Müller¹, Tatiana Cañeque¹, Ludovic Colombeau¹, Adam Huczyński², Michał Antoszczak^{1

2}, 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

As a continuation of our studies toward the development of small molecules to selectively target cancer stem cells (CSCs), a library of 18 novel derivatives of salinomycin (Sal), a naturally occurring polyether ionophore, was synthesized with a good overall yield using a one-pot Mitsunobu-Staudinger procedure. Compared to the parent structure, the newly synthesized products contained the mono- or disubstituted C20-epi-amine groups. The biological activity of these compounds was evaluated against human mammary mesenchymal HMLER CD24^low/CD44^high cells, a well-established model of breast CSCs, and its isogenic epithelial cell line (HMLER CD24^high/CD44^low) lacking CSC properties. Importantly, the vast majority of Sal derivatives were characterized by low nanomolar activities, comparing favorably with previous data in the literature. Furthermore, some of these derivatives exhibited a higher selectivity for the mesenchymal state compared to the reference Sal and ironomycin, representing a promising new series of compounds with anti-CSC activity.