Studies on Shape and Property Altering Polysubstitution Cascades

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.