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.
Centre for Analysis and Synthesis, Department of Chemistry, Lund University , Box 124, 221 00 Lund, Sweden.
Björn
B
Borgström
Department of Biology, Lund University , 221 00 Lund, Sweden.
Xiaoli
X
Huang
Centre for Analysis and Synthesis, Department of Chemistry, Lund University , Box 124, 221 00 Lund, Sweden.
Eduard
E
Chygorin
Department of Biology, Lund University , 221 00 Lund, Sweden.
Stina
S
Oredsson
Centre for Analysis and Synthesis, Department of Chemistry, Lund University , Box 124, 221 00 Lund, Sweden.
Daniel
D
Strand
ALDH+; head-to-tail conformation; hydroxamic acid derivative; salinomycin