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

Borgström, Björn LU ; Huang, Xiaoli LU ; Hegardt, Cecilia LU ; Oredsson, Stina LU and Strand, Daniel LU (2017) In Chemistry - A European Journal 23(9). p.2077-2083
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... (More)

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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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
cancer treatment, ionophores, phenotype selectivity, salinomycin, structure–activity relationships
in
Chemistry - A European Journal
volume
23
issue
9
pages
7 pages
publisher
John Wiley & Sons
external identifiers
  • scopus:85002654584
  • wos:000395755100016
ISSN
0947-6539
DOI
10.1002/chem.201603621
language
English
LU publication?
yes
id
2cb67c5e-878b-4c33-a207-0c011f8ff381
date added to LUP
2017-02-24 09:28:01
date last changed
2018-12-16 04:55:16
@article{2cb67c5e-878b-4c33-a207-0c011f8ff381,
  abstract     = {<p>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.</p>},
  author       = {Borgström, Björn and Huang, Xiaoli and Hegardt, Cecilia and Oredsson, Stina and Strand, Daniel},
  issn         = {0947-6539},
  keyword      = {cancer treatment,ionophores,phenotype selectivity,salinomycin,structure–activity relationships},
  language     = {eng},
  month        = {02},
  number       = {9},
  pages        = {2077--2083},
  publisher    = {John Wiley & Sons},
  series       = {Chemistry - A European Journal},
  title        = {Structure–Activity Relationships in Salinomycin : Cytotoxicity and Phenotype Selectivity of Semi-synthetic Derivatives},
  url          = {http://dx.doi.org/10.1002/chem.201603621},
  volume       = {23},
  year         = {2017},
}