Zong Guanghui, Barber Eric, Aljewari Hazim, Zhou Jianhong, Hu Zhijian, Du Yuchun, Shi Wei Q
Department of Chemistry and Biochemistry and ‡Department of Biological Sciences, J. William Fulbright College of Arts & Science, University of Arkansas , Fayetteville, Arkansas 72701, United States.
J Org Chem. 2015 Sep 18;80(18):9279-91. doi: 10.1021/acs.joc.5b01765. Epub 2015 Sep 4.
Ipomoeassin F, a macrolide glycoresin containing an embedded disaccharide, possesses potent in vitro antitumor activity with an unknown mechanism of function. It inhibits tumor cell growth with single-digit nanomolar IC50 values, superior to many clinical chemotherapeutic drugs. To facilitate translation of its bioactivity into protein function for drug development, we report here a new synthesis for the gram-scale production of ipomoeassin F (3.8% over 17 linear steps) from commercially available starting materials. The conformation-controlled subtle reactivity differences of the hydroxyl groups in carbohydrates were utilized to quickly construct the disaccharide core, which, along with judicial selection of protecting groups, made the current synthesis very efficient. The same strategy was also applied to the smooth preparation of the 11R-epimer of ipomoeassin F for the first time. Cytotoxicity assays demonstrated the crucial role of the natural 11S configuration. In addition, cell cycle analyses and apoptosis assays on ipomoeassin F and/or its epimer were conducted. This work has laid a solid foundation for understanding the medicinal potential of the ipomoeassin family of glycolipids in the future.
番薯素F是一种含有嵌入二糖的大环内酯糖脂，具有强大的体外抗肿瘤活性，但其作用机制尚不清楚。它以个位数纳摩尔的IC50值抑制肿瘤细胞生长，优于许多临床化疗药物。为了便于将其生物活性转化为药物开发中的蛋白质功能，我们在此报告一种新的合成方法，可从市售起始原料以克级规模生产番薯素F（17步线性反应产率为3.8%）。利用碳水化合物中羟基的构象控制的细微反应性差异快速构建二糖核心，再结合对保护基团的合理选择，使得当前合成非常高效。同样的策略也首次应用于番薯素F的11R-差向异构体的顺利制备。细胞毒性试验证明了天然11S构型的关键作用。此外，还对番薯素F及其差向异构体进行了细胞周期分析和凋亡试验。这项工作为未来理解番薯素糖脂家族的药用潜力奠定了坚实基础。
