Synthesis of Glycomimetics and Gycodendrimers of Biological Interests

具有生物学意义的糖模拟物和糖树大分子的合成

• 批准号: 1589-2013
• 负责人: Roy, René
• 金额: $ 3.21万
• 依托单位: Université du Québec à Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2017
• 资助国家: 加拿大
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=632761
• 关键词: Synthesis; Glycomimetics; Gycodendrimers; Biological; Interests

Cell-surface glycoconjugates are responsible for a wide range of biological interactions at the origin of pathologies. Unfortunately, the nature of the binding interactions is weak and poorly selective. The following integrated research program is aimed at using conceptually novel strategies toward the design of high affinity and specificity carbohydrate dendritic nanomaterials for the targeting of conceptually innovative carriers against cancer, bacterial and viral infections. The concept of dendrimer design will be expanded to include two new features that have been overlooked so far. The conservative and restrictive approaches to dendrimer syntheses will be changed by using different chemical motifs between each layer, thus offering additional controls into the desired biophysical properties. This innovative "onion-peel" approach will provide much greater flexibility in the synthetic schemes leading to the novel dendrimer architectures. In addition, the above modifications will be improved by providing dendrimers harboring two different surface moieties to ensure the most efficient bacterial and cancer cell targeting. This will be particularly exemplified with two types of bacteria such as P. aeruginosa and uropathogenic E. coli involved in cystic fibrosis and pyelonephritis. To integrate bactericidal properties within the nanomaterials, we also proposed to simultaneously include antibacterial agents. As an additional level of improvement in the design of novel glycodendrimers, we also propose to use medicinal chemistry methodologies through which, much better ligands candidates will become accessible. Using the above two variables (multivalency and glycomimetic), more reliable, low valency analogs will be secured. A particular emphasis will be given to organometallic and asymmetric chemistry in order to provide access to structures with key chiral centers. Spacer length, distances, hydro/lipo-philicity will all be factors to be optimized. A novel aspect will also concentrate on the syntheses of a new family of self-assembled molecules calles glycodendrimersomes.

细胞表面糖缀合物在病理起源中负责广泛的生物相互作用。不幸的是，结合相互作用的性质很弱，选择性很差。以下综合研究计划旨在使用概念上的新策略来设计高亲和力和特异性碳水化合物树突状纳米材料，用于靶向概念上的创新载体，以对抗癌症、细菌和病毒感染。树状结构设计的概念将被扩展到包括两个迄今为止被忽视的新特性。通过在每层之间使用不同的化学基序，将改变树状大分子合成的保守和限制性方法，从而为所需的生物物理特性提供额外的控制。这种创新的“洋葱皮”方法将为合成方案提供更大的灵活性，从而产生新的树突结构。此外，上述修饰将通过提供含有两种不同表面部分的树状大分子来改进，以确保最有效地靶向细菌和癌细胞。这将特别以两种类型的细菌为例，如铜绿假单胞菌和尿路致病性大肠杆菌参与囊性纤维化和肾盂肾炎。为了在纳米材料中整合杀菌性能，我们还建议同时加入抗菌剂。作为设计新型糖树状大分子的额外改进，我们还建议使用药物化学方法，通过这种方法，可以获得更好的候选配体。使用上述两个变量（多价和糖拟物），将获得更可靠的低价类似物。我们将特别强调有机金属化学和不对称化学，以便了解具有关键手性中心的结构。隔离剂的长度、距离、亲水/亲脂性都是需要优化的因素。一个新的方面也将集中在一个新的自组装分子家族称为糖树突状体的合成。