Structure–Activity Relationships in Salinomycin: Cytotoxicity and Phenotype Selectivity of Semi-synthetic Derivatives

Research output: Contribution to journalArticle

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.

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Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medicinal Chemistry
  • Cancer and Oncology

Keywords

  • cancer treatment, ionophores, phenotype selectivity, salinomycin, structure–activity relationships
Original languageEnglish
Pages (from-to)2077-2083
Number of pages7
JournalChemistry - A European Journal
Volume23
Issue number9
Publication statusPublished - 2017 Feb 10
Publication categoryResearch
Peer-reviewedYes