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

Authors:

• Dominika Czerwonka,
• Sebastian Müller,
• Tatiana Cañeque,
• Ludovic Colombeau,
• Adam Włodzimierz Huczyński,
• Michał Antoszczak,
• Raphaël Rodriguez

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 CD24low /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.