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Salinomycin Derivatives Kill Breast Cancer Stem Cells by Lysosomal Iron Targeting
Author(s) -
Versini Antoine,
Colombeau Ludovic,
Hienzsch Antje,
Gaillet Christine,
Retailleau Pascal,
Debieu Sylvain,
Müller Sebastian,
Cañeque Tatiana,
Rodriguez Raphaël
Publication year - 2020
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.202000335
Subject(s) - salinomycin , cd44 , cancer stem cell , cd24 , stem cell , chemistry , cancer research , cancer cell , biochemistry , cancer , biology , microbiology and biotechnology , in vitro , genetics , antibiotics
Salinomycin ( 1 ) exhibits a large spectrum of biological activities including the capacity to selectively eradicate cancer stem cells (CSC), making it and its derivatives promising candidates for the development of drug leads against CSC. It has been previously shown that salinomycin and its C20‐propargylamine derivative (Ironomycin ( 2 )) accumulate in lysosomes and sequester iron in this organelle. Herein, a library of salinomycin derivatives is reported, including products of C20‐amination, C1‐esterification, C9‐oxidation, and C28‐dehydration. The biological activity of these compounds is evaluated against transformed human mammary epithelial HMLER CD24 low /CD44 high cells, a well‐established model of breast CSC, and HMLER CD24 high /CD44 low cells deprived of CSC properties. Unlike other structural alterations, derivative 4 , which displays a cyclopropylamine at position C20, showed a strikingly low IC 50 value of 23 n m against HMLER CD24 low /CD44 high cells. This study provides highly selective molecules to target the CSC niche, a potential interesting advance for drug development to prevent cancer resistance.