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

癌症是全球主要的死亡原因，2008年有760万人死亡(约占所有死亡人数的13%)(世卫组织癌症，2012年)。据估计，全球每年有1270万癌症病例，预计到2030年，这一数字将增加到2600万。事实证明，除了手术外，化疗在治疗癌症方面也非常有用。然而，其有效性往往受到有用药物的数量和它们的毒性的限制。为了公众健康，治疗癌症总是需要设计有效的药物。在这里，我们报道了一种利用糖基化技术靶向热休克蛋白90 kDa(Hsp90)的新方法。HSP90介导蛋白质折叠，而蛋白质折叠对癌细胞的存活很重要。对Hsp90的抑制可能同时抑制对肿瘤生存至关重要的多个治疗靶点和途径。Novobiocin最初于20世纪60年代被批准用于临床，商标为阿巴霉素(Pharmacia和Upjohn)作为抗生素药物。最近，也有研究表明，Novobiocin通过与Hsp90结合而具有较低的抗癌活性。以前，对Hsp90的亲和力较差，而对II型拓扑异构酶的亲和力较高，这阻碍了新生物素作为临床有用的Hsp90抑制剂的评估。最近，我们证明了糖基化方法可以将抗癌活性从抗菌活性(作为拓扑异构酶的替代物)分离到27000倍，为抗癌药物的发现提供了一种有用的替代策略。然而，该药物如何与Hsp90 C末端相互作用的机制尚不完全清楚。糖基化新生物素的重要生物学作用表明，碳水化合物修饰是这些分子生物学功能的中心。我们认为，这些基于糖基的修饰策略是一条合理设计、修饰先导化合物和改变现有药物分子用途的潜在途径。

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.