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.