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Semisynthesis of SY-1 for Investigation of Breast Cancer Stem Cell Selectivity of C-Ring-Modified Salinomycin Analogues.

Huang, Xiaoli LU ; Borgström, Björn LU ; Månsson, Linda LU ; Persson, Lo LU ; Oredsson, Stina LU ; Hegardt, Cecilia LU and Strand, Daniel LU (2014) In ACS Chemical Biology 9(7). p.1587-1594
Abstract
Salinomycin, a naturally occurring polyether ionophore was recently found to selectively reduce the proportion of CD44(+)/CD24(-) cells, a phenotype associated with breast cancer stem cells. Subsequent studies from our group showed that chemical modification of the allylic C20 hydroxyl of salinomycin, located at the C-ring, can enhance the activity of derivatives against breast cancer cells over 5-fold compared to the native structure. Access to C-ring-modified salinomycin analogues is thus of interest from both a mechanistic and a synthetic perspective. Here, we report efficient strategies for gram scale synthesis of the natural product SY-1 (20-deoxy salinomycin), and a saturated analogue, 18,19-dihydro SY-1, for a comparative in vitro... (More)
Salinomycin, a naturally occurring polyether ionophore was recently found to selectively reduce the proportion of CD44(+)/CD24(-) cells, a phenotype associated with breast cancer stem cells. Subsequent studies from our group showed that chemical modification of the allylic C20 hydroxyl of salinomycin, located at the C-ring, can enhance the activity of derivatives against breast cancer cells over 5-fold compared to the native structure. Access to C-ring-modified salinomycin analogues is thus of interest from both a mechanistic and a synthetic perspective. Here, we report efficient strategies for gram scale synthesis of the natural product SY-1 (20-deoxy salinomycin), and a saturated analogue, 18,19-dihydro SY-1, for a comparative in vitro investigation of the biological profiles of these compounds with that of salinomycin. Across several assays, the deoxygenated structures required higher concentrations to elicit similar cellular responses to that of salinomycin. Similarly to salinomycin, SY-1 or 18,19-dihydro SY-1 treatment was found to reduce the proportion of CD44(+)/CD24(-) cells with essentially complete selectivity up to ∼IC25. Importantly, the proportion of CD44(+)/CD24(-) cells showed a pronounced U-shaped dose response curve for salinomycin and its derivatives, but not for paclitaxel. The concentration for maximum response in this assay followed differences in IC50 for salinomycin and its analogues, which emphasizes the importance of taking concentration dependence into account when comparing effects on the CD44(+)/CD24(-) phenotype. Small differences in the global conformation within the triad of compounds investigated together with differences in activity across assays emphasize the importance of substitution at C20 for the activity of salinomycin and its derivatives. (Less)
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author
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type
Contribution to journal
publication status
published
subject
in
ACS Chemical Biology
volume
9
issue
7
pages
1587 - 1594
publisher
The American Chemical Society
external identifiers
  • scopus:84904544019
  • pmid:24841425
  • wos:000339366600025
ISSN
1554-8937
DOI
10.1021/cb5002153
language
English
LU publication?
yes
id
5de19ba9-eaff-49ca-ac97-eb1c8cd37b51 (old id 7373420)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/24841425
date added to LUP
2015-06-23 14:59:47
date last changed
2017-10-01 03:00:48
@article{5de19ba9-eaff-49ca-ac97-eb1c8cd37b51,
  abstract     = {Salinomycin, a naturally occurring polyether ionophore was recently found to selectively reduce the proportion of CD44(+)/CD24(-) cells, a phenotype associated with breast cancer stem cells. Subsequent studies from our group showed that chemical modification of the allylic C20 hydroxyl of salinomycin, located at the C-ring, can enhance the activity of derivatives against breast cancer cells over 5-fold compared to the native structure. Access to C-ring-modified salinomycin analogues is thus of interest from both a mechanistic and a synthetic perspective. Here, we report efficient strategies for gram scale synthesis of the natural product SY-1 (20-deoxy salinomycin), and a saturated analogue, 18,19-dihydro SY-1, for a comparative in vitro investigation of the biological profiles of these compounds with that of salinomycin. Across several assays, the deoxygenated structures required higher concentrations to elicit similar cellular responses to that of salinomycin. Similarly to salinomycin, SY-1 or 18,19-dihydro SY-1 treatment was found to reduce the proportion of CD44(+)/CD24(-) cells with essentially complete selectivity up to ∼IC25. Importantly, the proportion of CD44(+)/CD24(-) cells showed a pronounced U-shaped dose response curve for salinomycin and its derivatives, but not for paclitaxel. The concentration for maximum response in this assay followed differences in IC50 for salinomycin and its analogues, which emphasizes the importance of taking concentration dependence into account when comparing effects on the CD44(+)/CD24(-) phenotype. Small differences in the global conformation within the triad of compounds investigated together with differences in activity across assays emphasize the importance of substitution at C20 for the activity of salinomycin and its derivatives.},
  author       = {Huang, Xiaoli and Borgström, Björn and Månsson, Linda and Persson, Lo and Oredsson, Stina and Hegardt, Cecilia and Strand, Daniel},
  issn         = {1554-8937},
  language     = {eng},
  number       = {7},
  pages        = {1587--1594},
  publisher    = {The American Chemical Society},
  series       = {ACS Chemical Biology},
  title        = {Semisynthesis of SY-1 for Investigation of Breast Cancer Stem Cell Selectivity of C-Ring-Modified Salinomycin Analogues.},
  url          = {http://dx.doi.org/10.1021/cb5002153},
  volume       = {9},
  year         = {2014},
}