Salinomycin Hydroxamic Acids: Synthesis, Structure, and Biological Activity of Polyether Ionophore Hybrids

The
polyether ionophore salinomycin has recently gained attention
due to its exceptional ability to selectively reduce the proportion
of cancer stem cells within a number of cancer cell lines. Efficient
single step strategies for the preparation of hydroxamic acid hybrids
of this compound varying in N- and O-alkylation are
presented. The parent hydroxamic acid, salinomycin-NHOH, forms both
inclusion complexes and well-defined electroneutral complexes with
potassium and sodium cations via 1,3-coordination by the hydroxamic
acid moiety to the metal ion. A crystal structure of an cationic sodium
complex with a noncoordinating anion corroborates this finding and,
moreover, reveals a novel type of hydrogen bond network that stabilizes
the head-to-tail conformation that encapsulates the cation analogously
to the native structure. The hydroxamic acid derivatives display down
to single digit micromolar activity against cancer cells but unlike
salinomycin selective reduction of ALDH+ cells, a phenotype
associated with cancer stem cells was not observed. Mechanistic implications
are discussed.