Studies on Shape and Property Altering Polysubstitution Cascades

在化学系化学合成项目的支持下，洛杉矶加州大学的帕特里克·哈伦教授正在研究氟化肽模拟物的开发，这些分子模拟天然肽的特性。环肽及其替代物在研究中是有价值的，因为它们作为药物发现的先导，作为化学生物学中的探针化合物以及作为材料科学的构建块。Harran及其同事正在开发新的合成工具，以创造一种以前未知的氟化环肽复合物。他们都在研究这些结构的三维结构及其物理特性。他们的方法平台能够系统地生成新分子，并有可能在未来推动许多合作研究。该项目涵盖了从合成到化学生物学再到医学的广泛的化学学科，其成果将影响化学，制药和材料行业。因此，这项工作非常适合培训和教育那些将在这些STEM（科学，技术，工程和数学）领域从事职业的年轻科学家。加州大学洛杉矶分校的Harran研究小组发现，含有半胱氨酸，酪氨酸，组氨酸和丝氨酸残基组合的肽与八氟环戊烯（OFCP）以相对速率控制的多取代级联反应。这些多阶段反应在0-25 ° C下在单个烧瓶中将线性、未受保护的底物转化为多环产物，而不使用催化剂或重金属。化学反应正在产生大量以前未知的杂环系统。根据该奖项，功能组的兼容性，环尺寸公差和相对速率差异管理效率的方式将被检查。大双环产物的稳定性、溶解性和构象行为也将被研究。将测试从支化位置引发反应级联，以及设计用于生成一类新的氟化“假”联芳基的变体。最后，将探索通过瞬时反应中间体来增强OFCP与分子插入物的支架能力以促进额外的大环化的方法。这项工作的首要目标是开发技术，使新的膜渗透结构模拟的主要蛋白质表面环类型中观察到的蛋白质数据库的合成。 如果成功，本文开发的OFCP-缝合化学将提供在化学生物学中潜在广泛用途的使能工具。该奖项反映了NSF的法定使命，并被认为值得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来支持。

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.