Synthesis of glycosyl-novobiocins: probes of Hsp90 C-terminal affinity binding and novel anti-cancer drugs

癌症是全球死亡的主要原因，2008年有760万人死亡（约占所有死亡人数的13%）（WHO癌症，2012）。据估计，全世界每年有1270万例癌症病例，到2030年，这一数字预计将增加到2600万例。然而，其有效性往往受到有用药物数量及其毒性的限制。设计有效的药物总是需要治疗癌症的公共卫生。在这里，我们报告了一种新的方法，利用糖基化技术靶向热休克蛋白90 kDa（Hsp 90）。Hsp 90介导蛋白质折叠，这对癌细胞存活很重要。对Hsp 90的抑制可以同时抑制多个治疗靶点和对肿瘤存活至关重要的途径。新生霉素最初在20世纪60年代以Albamycin（Pharmacia和Upjohn）的商品名被批准作为抗生素药物用于临床。最近，新生霉素也已显示通过与Hsp 90结合而具有低抗癌活性。以前，对Hsp 90的差的亲和力和对II型拓扑异构酶的较高亲和力阻止新生霉素被评价为临床有用的Hsp 90抑制剂。最近，我们证明了糖基化方法可以将抗癌活性与抗菌活性（作为拓扑异构酶的代表）分离27，000倍，为抗癌药物发现提供了有用的替代策略。然而，药物如何与Hsp 90 C-末端相互作用的机制尚不完全清楚。糖基化新生生物素的重要生物学作用表明，碳水化合物修饰对这些分子的生物学功能至关重要。我们认为，这些基于糖基的修饰策略是合理设计、修饰先导化合物和重新利用现有药物分子的潜在途径。

Cancer is a leading cause of death worldwide, accounting for 7.6 million deaths (around 13% of all deaths) in 2008 (WHO cancer, 2012). There are an estimated 12.7 million cancer cases around the world every year, and this number expected to increase to 26 million by 2030.Chemotherapy has proven to be very useful in addition to surgery in treating cancer. However, its effectiveness is often limited with the number of useful drugs and their toxicities. Designing effective drugs are always required to treat cancer for public health. Here we report a new approach to target Heat Shock Protein 90 kDa (Hsp90) using glycosylation technology. Hsp90 mediates protein folding which is important to cancer cell survival. Inhibition to Hsp90 maysimultaneously inhibit multiple therapeutic targets and pathways crucial to tumour survival.Novobiocin was originally approved for clinical use in the 1960s under the trade name Albamycin (Pharmacia and Upjohn) as an antibiotic drug. Recently, Novobiocin has also been shown to have low anticancer activity via binding to Hsp90. Previously, the poor affinity to Hsp90 and higher affinity for type-II topoisomerases prevented novobiocin being evaluated as a clinical useful Hsp90 inhibitor. Recently, we demonstrated that a glycosylation approach can separate the anti-cancer activity from the antibacterial activity (as a proxy of topoisomerase) to 27,000 fold providing a useful alternative strategy for anti-cancer drug discovery. However, the mechanism on how the drug interacts with Hsp90 C-terminal is not fully clear. The important biological roles of glycosylated novobiocins suggest that carbohydrate modifications are central to the biological function of these molecules. We propose that these glycosyl-based modification strategies are a potential route to the rational design, modification of lead compounds and repurposing of existing drug molecules.