Institut Curie, 26 rue d'Ulm, 75248, Paris Cedex 05, France.
PSL Université, 60 rue Mazarine, 75006, Paris, France.
Chemistry. 2020 Jun 10;26(33):7416-7424. doi: 10.1002/chem.202000335. Epub 2020 Apr 17.
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 /CD44 cells, a well-established model of breast CSC, and HMLER CD24 /CD44 cells deprived of CSC properties. Unlike other structural alterations, derivative 4, which displays a cyclopropylamine at position C20, showed a strikingly low IC value of 23 nm against HMLER CD24 /CD44 cells. This study provides highly selective molecules to target the CSC niche, a potential interesting advance for drug development to prevent cancer resistance.
盐霉素（1）表现出广泛的生物活性，包括选择性根除癌症干细胞（CSC）的能力，使其及其衍生物成为开发针对 CSC 的药物先导物的有前途的候选物。先前已经表明，盐霉素及其 C20-炔丙胺衍生物（Ironomycin（2））在溶酶体中积累，并在该细胞器中隔离铁。本文报道了一系列盐霉素衍生物，包括 C20-胺化、C1-酯化、C9-氧化和 C28-脱水产物。这些化合物的生物学活性针对转化的人乳腺上皮 HMLER CD24 / CD44 细胞进行了评估，HMLER CD24 / CD44 细胞是乳腺癌 CSC 的成熟模型，以及失去 CSC 特性的 HMLER CD24 / CD44 细胞。与其他结构改变不同，在 C20 位显示环丙基胺的衍生物 4 对 HMLER CD24 / CD44 细胞表现出极低的 IC 值（23nm）。这项研究提供了针对 CSC 生态位的高选择性分子，这可能是开发药物以预防癌症耐药性的一个有趣进展。
