title: Structure-Activity Relationships in Salinomycin: Cytotoxicity and Phenotype Selectivity of Semi-synthetic Derivatives.
abstract: The ionophore salinomycin has attracted attention for its exceptional ability to selectively reduce the proportion of cells with stem-like properties in cancer cell populations of varying origin. Targeting the tumorigenicity of such cells is of interest as they are implicated in recurrence, metastasis, and drug resistance. Structural derivatives of salinomycin are thus sought after, both as tools for probing the molecular mechanism(s) underlying the observed phenotype effects, and for improving selectivity and activity against cancer stem cells. Synthetic strategies for modification of each of the directly accessible functional groups of salinomycin are presented and the resulting library of analogues was investigated to establish structure-activity relationships, both with respect to cytotoxicity and phenotype selectivity in breast cancer cells. 20-O-Acylated derivatives stand out by exhibiting both improved selectivity and activity. Mechanistically, the importance of the ionophore properties of salinomycin is highlighted by a significant loss of activity by modifications directly interfering with either of the two primary ion coordinating motifs in salinomycin, the C11 ketone and the C1 carboxylate.
authors.affiliation: Centre for Analysis and Synthesis, Lund University, Box 124, 22100, Lund, Sweden.
authors.forename: Björn
authors.initials: B
authors.lastname: Borgström
authors.affiliation: Department of Biology, Lund University, Sölvegatan 35/37, 223 62, Lund, Sweden.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Huang
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Medicon Village, 223 81, Lund, Sweden.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Hegardt
authors.affiliation: Department of Biology, Lund University, Sölvegatan 35/37, 223 62, Lund, Sweden.
authors.forename: Stina
authors.initials: S
authors.lastname: Oredsson
authors.affiliation: Centre for Analysis and Synthesis, Lund University, Box 124, 22100, Lund, Sweden.
authors.forename: Daniel
authors.identifier: http://orcid.org/0000-0002-6113-4657
authors.initials: D
authors.lastname: Strand
keywords: cancer treatment; ionophores; phenotype selectivity; salinomycin; structure-activity relationships