Synthesis of Glycomimetics and Gycodendrimers of Biological Interests

细胞-表面糖偶联物在病理起源时负责广泛的生物相互作用。不幸的是，结合作用的性质是弱的和选择性差的。下面的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的碳水化合物树枝状纳米材料，用于靶向治疗癌症、细菌和病毒感染的概念创新载体。树枝状大分子设计的概念将扩大到包括两个迄今被忽视的新功能。树枝状大分子合成的保守和限制性方法将通过在每一层之间使用不同的化学基序来改变，从而为所需的生物物理性质提供额外的控制。这种创新的“洋葱皮”方法将在合成方案中提供更大的灵活性，从而导致新的树枝状大分子结构。此外，通过提供含有两种不同表面部分的树枝状大分子来改进上述修饰，以确保最有效的细菌和癌细胞靶向。这一点将特别以两种细菌为例，如铜绿假单胞菌和致尿系大肠杆菌，它们涉及囊性纤维化和肾盂肾炎。为了将杀菌性能整合到纳米材料中，我们还建议同时加入抗菌剂。作为新型糖树状大分子设计的额外改进，我们还建议使用药物化学方法，通过这种方法，更好的候选配体将变得容易获得。使用上述两个变量(多价态和拟糖基)，将获得更可靠的低价类似物。将特别强调有机金属和不对称化学，以便提供获得具有关键手性中心的结构的途径。间隔基团的长度、距离、亲水性/亲脂性都将是需要优化的因素。一个新的方面也将集中在一种新的自组装分子家族的合成上，称为糖树状聚合体。

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.