Development of SN2-type Glycosylation for Automated Glycan Synthesis

在化学系化学合成项目的支持下，加州大学圣巴巴拉分校的张黎明教授正在研究一种在适合自动合成聚糖的条件下选择性地将不同的糖分子连接在一起的方法。聚糖及其缀合形式（如糖蛋白、糖肽和糖脂等）是包含许多相互连接的糖单位的复杂分子，涉及多种生物过程和病理事件，包括：信号转导、受精、癌症转移、细胞-细胞粘附和免疫反应。研究聚糖和聚糖偶联物的生物学功能对于控制各种疾病和促进医学治疗至关重要，但这些努力受到制备明确的聚糖用于研究的困难的阻碍。正在开发的方法有可能帮助缓解聚糖研究中的瓶颈，通过实现以纯形式自动制备广泛的其他难以获得的聚糖结构。预计这项工作将反过来加速基于聚糖的疫苗和药物制剂的开发。由于张教授参与了一系列的教育活动，包括他将为进行研究的研究生同事提供严格的培训，因此，受资助项目的更广泛影响将扩大到为社会带来的利益。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，一旦加入私营企业或学术界的劳动力队伍，他们很可能对国家的科学事业做出宝贵的贡献。大学本科生，特别是那些在物理科学领域代表性不足的学生，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性和支持性经验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）方面的职业。该资助项目的重点是研究和进一步发展糖基化的导向基-离开基（DGLG）策略，在该策略中，糖基供体在C1位置上配备了可激活的核苷片段，通过立体可逆的亲核取代与糖基受体结合。类似sn2的糖基化是由一个接受氢键的基团引导和促进/加速的，这个接受氢键的基团促进亲核试剂在亲电试剂中弱键上的反共线攻击轨迹。该研究的目标分为三个连续阶段：(1)为基于DGLG策略的糖基化反应开发改进的反应条件和下一代离去基，这些反应既适用于固相合成，也适用于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-顺式，1,2-反式，2-脱氧α，2-脱氧β）；(2)在固相上验证和实施所开发的工艺；(3)在商业上可用的自动聚糖合成平台上演示这些过程的可行性。预计该研究将在复杂碳水化合物合成的理论和实践方面取得根本性进展，并且由此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。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值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.