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Molecular Amalgamations that Generate Constrained Peptidomimetic Macrocycles

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Peptidomimetic macrocycles are increasingly growing as attractive scaffolds for the development of therapeutics targeting protein-protein interactions. Compounds of this type have been traditionally underrepresented in drug discovery platforms due to their structural characteristics not conforming to typical guidelines for ‘drug-likeness’. We have developed methods to simultaneously investigate new bioactive chemotypes and their pharmacological properties in a systematic manner. Several libraries of peptidyl macrocyclic and polycyclic compounds are examined here based on previously developed template methodology and novel discoveries using a highly reactive fluorinated reagent. Both methods allow us to rapidly build complexity from machine made, protecting-group-free bioactive starting materials. In this way, we can efficiently and broadly survey the chemical space of macrocycles through a diversity-oriented strategy.

In Chapter 2, we show that unprotected peptides react with commercial octafluorocyclopentene (OFCP) to afford hexafluorinated macrocycles via successive ipso substitutions of vinyl fluoride. Sequence variants having combinations of cysteine, tyrosine, histidine, and serine residues are shown to react rapidly at room temperature to give stable, isolable products. We also introduce our initial discoveries involving polysubstitution cascades with OFCP.

Chapter 3 details a broad scope of polycyclic compounds provided directly through one-pot methods. Macrocycle and spirocycle variations are also examined. We found the vinyl fluoride position to be amenable to linker systems that provide access to polycycles incorporating previously unused amino acid residues. Non-cell-based permeability assays are performed to evaluate the properties of these structures.

In Chapter 4, using cell-based permeability assays we study the pharmacological properties of macrocycles incorporating various template generations derived from a core cinnamyl alcohol motif. Structure-permeability relationships are explored with these compounds systematically via a small library.

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This item is under embargo until December 8, 2024.