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

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 (), 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--amine groups. The biological activity of these compounds was evaluated against human mammary mesenchymal HMLER CD24/CD44 cells, a well-established model of breast CSCs, and its isogenic epithelial cell line (HMLER CD24/CD44) lacking CSC properties. Importantly, the vast majority of 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 and ironomycin, representing a promising new series of compounds with anti-CSC activity.