Semisynthesis of SY-1 for Investigation of Breast Cancer Stem Cell Selectivity of C-Ring-Modified Salinomycin Analogues
Semisynthesis of SY-1 for Investigation of Breast Cancer Stem Cell Selectivity of C-Ring-Modified Salinomycin Analogues
复制标题
DOI：
10.1021/cb5002153
复制
发表时间：
2014-07-01
影响因子：
4
通讯作者：
Strand, Daniel
中科院分区：
文献类型：
--
作者：
Huang, Xiaoli;Borgstrom, Bjorn;Strand, Daniel
盐霉素是一种天然存在的聚醚离子载体，最近发现可选择性降低CD 44（+）/CD 24（-）细胞的比例，这是一种与乳腺癌干细胞相关的表型。我们小组的后续研究表明，化学修饰盐霉素的烯丙基C20羟基，位于C环，可以增强衍生物对乳腺癌细胞的活性超过5倍的天然结构相比。因此，从机理和合成的角度来看，获得C环修饰的盐霉素类似物是令人感兴趣的。在这里，我们报告了有效的策略，克规模合成的天然产物SY-1（20-脱氧盐霉素），和饱和的类似物，18，19-二氢SY-1，这些化合物的生物学特性与盐霉素的比较在体外调查。在几个试验中，脱氧结构需要更高的浓度来引起与盐霉素类似的细胞反应。与盐霉素类似，发现SY-1或18，19-二氢SY-1处理降低了CD 44（+）/CD 24（-）细胞的比例，基本上完全选择性高达与IC 25相似。重要的是，CD 44（+）/CD 24（-）细胞的比例对盐霉素及其衍生物显示出明显的U形剂量反应曲线，但对紫杉醇没有。本试验中的最大响应浓度遵循盐霉素及其类似物的IC 50差异，这强调了在比较对CD 44（+）/CD 24（-）表型的影响时考虑浓度依赖性的重要性。研究的化合物的三联体内的全局构象的微小差异以及跨测定的活性差异强调了在C20处取代盐霉素及其衍生物的活性的重要性。
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 similar 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.