Salinomycin analogs: Mechanistic probes and structure–activity relationships against cancer stem cells

Björn Borgström

Research output: ThesisDoctoral Thesis (compilation)

Abstract

Cancer stem cells are a subpopulation of cells that possess an increased tumorigenic potential. Such cells are connected to drug resistance, metastasis, and cancer recurrence. In 2009, the polyether ionophore salinomycin was shown to exhibit selective activity against cancer stem cells. At the outset of the studies described in this thesis, few salinomycin analogs had been reported and it was not known if structural modifications could be used to enhance the activity against cancer stem cells. In addition, the molecular basis for the cancer stem cell selective activity of salinomyin was unknown.

This thesis describes the development of methods for semi–synthesis of salinomycin analogs, and the results of a biological evaluation of a library of such analogs in breast cancer cells. Acylation of the C20 hydroxyl group of salinomycin was shown to give structures with enhanced basal toxicity and increased activity against putative breast cancer stem cells. In both functional and marker based assays, the most active analogs gave pronounced effects on the putative cancer stem cell population already at 50 nM concentrations where salinomycin itself did not. Towards a molecular basis of the enhanced activity the structural and ionophore properties of a selection of the most active analogs were investigated. Preparation of a functionally competent fluorescent salinomycin conjugate and its use in a mechanistic investigation is also described.
Original languageEnglish
QualificationDoctor
Awarding Institution
  • Faculty of Science
Supervisors/Advisors
  • Strand, Daniel, Supervisor
Award date2016 Sept 30
Place of PublicationLund
Publisher
ISBN (Print)978-91-7422-472-6
Publication statusPublished - 2016 Sept

Bibliographical note

Defence details
Date: 2016-09-30
Time: 13:00
Place: Center for chemistry and chemical engineering, lecture hall C, Naturvetarvägen 14, Lund
External reviewer(s)
Name: Kirschning, Andreas
Title: Prof. Dr.
Affiliation: Leibniz University of Hannover, Germany
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Subject classification (UKÄ)

  • Organic Chemistry

Free keywords

  • salinomycin
  • semi–synthesis
  • ionophore properties
  • cancer stem cells
  • fluorescent probe

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