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

糖基新生霉素的合成：Hsp90 C 端亲和结合探针和新型抗癌药物

• 批准号: EP/K023071/1
• 负责人: Min Yang
• 金额: $ 12.63万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FK023071%2F1
• 关键词: Synthesis; glycosyl; novobiocins; probes; Hsp90

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.

癌症是全球死亡的主要原因，2008年占死亡人数为760万（占所有死亡人数的13％）（Who Cancer，2012年）。每年估计全球有1,270万例癌症病例，到2030年，这一数字预计将增加到2600万个癌症病例。除了治疗癌症外科手术外，化学疗法已被证明非常有用。但是，其有效性通常受到有用的药物及其毒性的限制。始终需要设计有效的药物来治疗癌症以治疗公共卫生。在这里，我们报告了一种使用糖基化技术靶向热激蛋白90 kDa（HSP90）的新方法。 HSP90介导蛋白质折叠，这对癌细胞的存活很重要。对HSP90 Maysimultane的抑制会抑制多种治疗靶标和对肿瘤存活至关重要的途径。新摩西蛋白最初被批准在1960年代以抗生素药物为抗生素。最近，通过与HSP90结合，Novobiocin还显示出低抗癌活性。以前，对HSP90的亲和力较差，对II型拓扑异构酶的亲和力较高，可阻止将Novobiocin评估为临床有用的HSP90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理）分离为27,000倍，从而为抗癌药物发现提供了有用的替代策略。但是，有关该药物如何与HSP90 C末端相互作用的机制尚不完全清楚。糖基化的新近苯胺的重要生物学作用表明，碳水化合物的修饰对于这些分子的生物学功能至关重要。我们建议这些基于糖基的修饰策略是通往合理设计的潜在途径，铅化合物的修饰和现有药物分子的重新塑造。

项目成果

Synthesis and characterization of photoaffinity labelling reagents towards the Hsp90 C-terminal domain.

针对 Hsp90 C 末端结构域的光亲和标记试剂的合成和表征。

• DOI: 10.1039/c6ob02097f
• 发表时间: 2017
• 期刊: Organic & biomolecular chemistry
• 影响因子: 3.2
• 作者: Simon B

Noninvasive imaging of sialyltransferase activity in living cells by chemoselective recognition.

通过化学选择性识别对活细胞中唾液酸转移酶活性进行无创成像

• DOI: 10.1038/srep10947
• 发表时间: 2015-06-05
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Bao L;Ding L;Yang M;Ju H
• 通讯作者: Ju H

Regioselective glycosylation of novobiocin alters activity.

新生霉素的区域选择性糖基化会改变活性。

• DOI: 10.1016/j.carres.2017.10.011
• 发表时间: 2017
• 期刊: Carbohydrate research
• 影响因子: 3.1
• 作者: Sun G

Protein-specific Raman imaging of glycosylation on single cells with zone-controllable SERS effect.

• DOI: 10.1039/c5sc03560k
• 发表时间: 2016-01-01
• 期刊: Chemical science
• 影响因子: 8.4
• 作者: Chen Y;Ding L;Song W;Yang M;Ju H
• 通讯作者: Ju H

Micro-competition system for Raman quantification of multiple glycans on intact cell surface.

• DOI: 10.1039/c5sc01031d
• 发表时间: 2015-07-01
• 期刊: Chemical science
• 影响因子: 8.4
• 作者: Chen Y;Ding L;Xu J;Song W;Yang M;Hu J;Ju H
• 通讯作者: Ju H