Development of SN2-type Glycosylation for Automated Glycan Synthesis

在化学系化学合成计划的支持下，加州大学圣巴巴拉分校的张黎明教授正在研究一种方法，在适合于自动合成多糖的条件下，将不同的糖分子选择性地连接在一起。多聚糖及其结合形式(如糖蛋白、糖肽和糖脂等)是含有许多相互关联的糖单元的复杂分子，涉及多种生物学过程和病理事件，包括：信号转导、受精、癌症转移、细胞-细胞黏附和免疫反应。研究葡聚糖及其结合物的生物学功能对于控制各种疾病和促进医学治疗是必不可少的，但由于难以制备明确定义的葡聚糖用于研究，这些努力受到了阻碍。正在开发的方法有可能帮助缓解葡聚糖研究的瓶颈，因为它能够自动制备一系列原本无法获得的纯形式的葡聚糖结构。预计这项工作将反过来加速以葡聚糖为基础的疫苗和药物的开发。该资助项目的更广泛影响延伸到了随着张教授参与一系列教育活动而为社会带来的好处，包括他将为进行研究的研究生同事提供严格的培训。这些人将获得先进的有机化学知识，同时获得执行复杂合成操作所需的技能，在加入私营行业或学术界的劳动力大军后，他们很可能在未来为国家的科学事业做出宝贵贡献。本科生，特别是那些在物理科学中代表性较低的群体，也将被招募来帮助研究工作；学生在实验室环境中获得的包容和支持性的经验预计将鼓励他们考虑更高的教育目标和/或科学、技术、工程和数学(STEM)的职业。资助的项目侧重于研究和进一步发展糖基化的指导基团(DGLG)策略，在该策略中，糖基供体在C1位配备了可激活的核疏水基团，通过主要是立体可逆的亲核取代反应与糖基受体接触。SN2-样糖基化由异构体离开基团中的氢键接受基团指导和促进/加速，该氢键接受基团促进亲核剂对亲电体中弱键的反共线攻击轨迹。研究目标分为三个连续阶段：(1)开发改进的反应条件和新一代基于DGLG策略的糖基化反应的离基，这些反应适合于固相合成，但仍然适用于几乎任何类型的糖苷键的立体选择性形成(即，吡喃糖或呋喃糖体系中的1，2-顺、1，2-反式、2-脱氧-α、2-脱氧-β类型)；(2)验证和实施开发的固相工艺；(3)在商业上可用的糖链自动化合成平台上展示这些工艺的可行性。预计这项研究将导致复杂碳水化合物合成理论和实践的根本性进步，以及由这些发现产生的新兴技术将对糖生物学和药物化学等辅助学科产生影响。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

With the support of the Chemical Synthesis Program in the Division of Chemistry, Professor Liming Zhang of the University of California at Santa Barbara is studying a method that selectively links together different sugar molecules under conditions suitable for the automated synthesis of glycans. Glycans and their conjugated forms (e.g., glycoproteins, glycopeptides, and glycolipids etc.) are complex molecules containing many interlinked sugar units that are implicated in a variety of biological processes and pathological events, including: signal transduction, fertilization, cancer metastasis, cell-cell adhesion, and immune responses. Investigations of the biological functions of glycans and glycan conjugates are essential for managing various diseases and for the advancement of medical treatments, but these endeavors are hindered by the difficulty of preparing well-defined glycans for study. The method being developed has the potential to help alleviate bottlenecks in glycan research by enabling automated preparations of a broad range of otherwise inaccessible glycan structures in pure form. It is anticipated that this work will in turn accelerate the development of glycan-based vaccines and pharmaceutical agents. The broader impacts of the funded project extend to the benefits accrued to society as Professor Zhang engages in a range of educational activities including the rigorous training that he will provide to the graduate student coworkers conducting the research. These individuals, who will gain knowledge of advanced organic chemistry while acquiring the skills necessary to perform complex synthetic operations, are likely to make valuable future contributions to the Nation's scientific enterprise upon joining the workforce in private industry or academia. Undergraduate students, especially those belonging to groups underrepresented in the physical sciences, will also be recruited to help with the research effort; the inclusive and supportive experiences that the students gain in the laboratory environment are anticipated to encourage them to consider higher educational goals and/or careers in science, technology, engineering, and mathematics (STEM).The funded project focuses on the study and further development of the directing-group-on-leaving-group (DGLG) strategy for glycosylation in which glycosyl donors equipped with activatable nucleofugal moieties at the C1 position engage with glycosyl acceptors via largely stereoinvertive nucleophilic substitution. The SN2-like glycosylation is directed and facilitated/accelerated by a hydrogen bond-accepting group within the anomeric leaving group that promotes an anti-colinear attack trajectory of the nucleophile upon the weakened bond in the electrophile. The aims of the research are divided into three sequential phases: (1) development of improved reaction conditions and next-generation leaving groups for DGLG strategy-based glycosylation reactions that are appropriate for solid phase synthesis and yet are still applicable for the stereoselective formation of essentially any type of glycosidic bond (i.e., 1,2-cis, 1,2-trans, 2-deoxy-alpha, 2-deoxy-beta types in pyranose or furanose systems); (2) validation and implementation of the developed processes on the solid phase; and (3) demonstration of the feasibility of the processes in a commercially available platform for automated glycan synthesis. It is anticipated that the research will lead to fundamental advances in the theory and practice of complex carbohydrate synthesis and that the emergent technology arising from the discoveries will be impactful to ancillary disciplines such as glycobiology and medicinal chemistry.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.