Studies on Shape and Property Altering Polysubstitution Cascades

在化学系化学合成计划的支持下，加州大学洛杉矶分校的帕特里克·哈伦教授正在研究氟化肽模拟物的发展，这种分子模仿自然产生的多肽的性质。环肽及其替代物在研究中具有重要价值，因为它们是药物发现的先导，是化学生物学中的探针化合物，也是材料科学的基石。哈伦和他的同事们正在开发新的合成工具，以创建一类以前未知的含氟环肽复合材料。他们都在研究这些结构的三维结构及其物理性质。他们的方法平台能够系统地产生新的分子，并有潜力推动未来的许多合作研究。该项目跨越了从合成到化学生物学再到医学的广泛化学学科，其结果将影响化学、制药和材料行业。因此，这项工作非常适合培养和教育年轻的科学家，他们将继续在这些STEM(科学、技术、工程和数学)领域的职业生涯。加州大学洛杉矶分校的Harran研究团队发现，含有半胱氨酸、酪氨酸、组氨酸和丝氨酸残基的多肽与八氟环戊烯(OFCP)在相对速率控制的多取代级联反应中。这些多阶段反应在0-25˚C的单个烧瓶中将无保护的线性底物转化为多环产物，无需使用催化剂或重金属。这种化学正在产生大量以前不为人知的杂环体系。根据这一奖项，将审查功能组兼容性、环大小公差和相对速率差异管理效率的方式。还将研究大双环产品的稳定性、溶解性和构象行为。将测试从分支位置引发的反应级联，以及设计用于生成一类新的氟化‘拟’-联芳基的变体。最后，将探索通过瞬时反应中间体来增强OFCP的支架能力的方法，以促进额外的大环化。这项工作的总体目标是开发能够合成蛋白质数据库中观察到的主要蛋白质表面环类型的新的膜结构模拟物的技术。如果成功，这里正在开发的OFCP装订化学将提供一种在化学生物学中具有潜在广泛用途的使能工具。这一奖项反映了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 Patrick Harran of the University of California, Los Angeles is studying the development of fluorinated peptidomimetics, molecules that mimic the properties of naturally occurring peptides. Cyclic peptides and their surrogates are valuable in research in that they serve as leads in drug discovery, as probe compounds in chemical biology and as building blocks for materials science. Harran and co-workers are developing new synthetic tools to create a previously unknown class of fluorinated cyclic peptide composites. They are both studying the three-dimensional structure of these constructs and their physical properties. Their methods platform is able to generate new molecules systematically, and it has the potential to drive many collaborative studies in the future. This project spans a broad range of chemical disciplines from synthesis to chemical biology to medicine and the outcomes will affect the chemical, pharmaceutical, and materials industries. Consequently, this work is well suited for training and educating young scientists who will go on to careers in these STEM (science, technology, engineering and mathematics) fields.The Harran research team at UCLA has discovered that peptides containing combinations of cysteine, tyrosine, histidine, and serine residues react with octafluorocyclopentene (OFCP) in relative rate controlled polysubstitution cascades. These multi-stage reactions convert linear, unprotected substrates into polycyclic products in a single flask at 0-25 ˚C without the use of catalysts or heavy metals. The chemistry is generating a wealth of previously unknown heterocyclic ring systems. Under this award, functional group compatibilities, ring size tolerances and the manner in which relative rate differentials govern efficiency will be examined. The stability, solubility and conformational behavior of macrobicyclic products will also be studied. Initiating reaction cascades from branching positions will be tested as will variants designed to generate a new class of fluorinated ‘pseudo’-biaryls. Lastly, methods to augment the scaffolding abilities of OFCP with molecular inserts to facilitate additional macrocyclizations via transient reactive intermediates will be explored. The overarching goal of this work is to develop technology that will enable the synthesis of new membrane permeant structural mimics of the major protein surface loop types observed in the Protein Data Bank. If successful, the OFCP-stapling chemistry being developed herein will provide an enabling tool of potentially wide utility in chemical biology. particularly for the burgeoning cyclic peptide field.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.