New approaches for the stereoselective synthesis of glycans of therapeutic interest

现在人们认识到，碳水化合物及其结合物参与了大量重要的生物过程，如免疫反应和细菌感染。为了深入了解这些机制以及开发以糖为基础的药物，迫切需要定义明确的葡聚糖。在过去的几年里，化学合成的进步使得制备不受生物污染的复合多糖成为可能，其中一些已经被批准用于治疗。然而，碳水化合物化学家仍然面临着重要的挑战，例如需要非传统和环保的合成路线，以及缺乏形成糖苷键的一般程序。我们研究计划的长期目标是开发新的和直接的合成方法来获得有治疗意义的寡糖和糖结合物。我们的第一个研究主题是通过创新的“程序化”糖基化反应，实现海绵衍生的具有独特结构特征的糖脂的全合成。在新西兰珊瑚礁的海绵中发现了这些糖脂，但由于天然来源的稀缺加上繁琐的纯化程序，这些糖脂的药理潜力尚未被探索。根据糖的不同反应性，糖脂将以最少的步骤合成，并在体外对其生物活性(抗癌、抗生素、免疫刺激)进行评估。在第二个研究主题中，将开发新的糖基化方法来合成非典型构型的细菌糖，并研究反应机理。这些方法将用于制备生物相关的多糖，如人类病原菌表面多糖中的七糖苷和Kdo糖苷。潜在的生物恐怖主义威胁假性伯克霍尔德氏菌、世界上导致细菌性腹泻的空肠弯曲杆菌以及脑膜炎的病原体脑膜炎奈瑟菌都在其表面表达这些糖。作为毒力因子和保护性抗原，七糖苷和Kdo糖苷的合成仍然是化学家的难题。因此，我们建议通过开发通用和有效的合成路线来访问它们来应对这一挑战。通过提供快速和环保的糖基化方法，打破传统的方法，我们的工作将有助于使该领域的非专家能够合成复杂的多糖。除了加强有机化学的基础科学知识外，拟议的研究计划还可能引发糖基药物的发现，这些药物可能会被应用于治疗人类疾病、杀死抗药性病原体，以及开发新的佐剂、诊断和疫苗。

It is now recognized that carbohydrates and their conjugates are involved in a plethora of important biological processes such as the immune response and bacterial infections. Well-defined glycans are urgently needed for the in-depth understanding of these mechanisms as well as for the development of sugar-based medicines. In the last years, advances in chemical synthesis have made possible the preparation of complex glycans free from biological contaminants, some of which have been approved as therapeutics. However, carbohydrate chemists are still facing important challenges such as the need for non-traditional and eco-friendly synthetic routes as well as the lack of general procedures for the formation of glycosidic bonds. The long-term goal of our research program is to develop novel and straightforward synthetic approaches to access oligosaccharides and glycoconjugates of therapeutic interest. Our first research theme is to achieve the total synthesis of sponge-derived glycolipids of unique structural features following an innovative “programmed” glycosylation reaction. Found within marine sponges of the New Zealand coral reef, the pharmacological potential of these glycolipids has yet to be explored due to the scarcity of the natural source coupled with the tedious purification procedures. The glycolipids will be synthesized in a minimal number of steps based on the differential reactivity of sugars and evaluated in vitro for their biological activities (anticancer, antibiotic, immunostimulant). In a second research theme, novel glycosylation methodologies for the synthesis of bacterial sugars of atypical configurations will be developed and the reaction mechanisms studied. These methods will be applied to the preparation of biologically relevant glycans, such as heptosides and Kdo glycosides, found in the surface polysaccharides of human pathogenic bacteria. Burkholderia pseudomallei, a potential bioterrorism threat, Campylobacter jejuni, the world's leading cause of bacterial diarrhea, as well as Neisseria meningitidis, the causative agent of meningitis, are all expressing these sugars on their surface. Considered as virulence factors and protective antigens, the synthesis of heptosides and Kdo glycosides is still problematic for chemists. We thus propose to tackle this challenge by developing general and efficient synthetic routes to access them. By providing rapid and eco-friendly glycosylation methodologies, breaking with classical approaches, our work will help make accessible the synthesis of complex glycans by non-experts in the field. In addition to enhance the fundamental scientific knowledge in organic chemistry, the proposed research program could trigger the discovery of sugar-based medicines that could find applications to treat human diseases, to kill resistant pathogens and to develop novel adjuvants, diagnostics and vaccines.