Large ring-forming alkylations provide facile access to composite macrocycles
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Authors: | Tristan E Rose Kenneth V Lawson Patrick G Harran |
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Institution: | a Department of Chemistry and Biochemistry , University of California Los Angeles , 607 Charles E. Young Drive East , Los Angeles , USA . Email: |
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Abstract: | Macrocyclic compounds have potential to enable drug discovery for protein targets with extended, solvent-exposed binding sites. Crystallographic structures of peptides bound at such sites show strong surface complementarity and frequent aromatic side-chain contacts. In an effort to capture these features in stabilized small molecules, we describe a method to convert linear peptides into constrained macrocycles based upon their aromatic content. Designed templates initiate the venerable Friedel–Crafts alkylation to form large rings efficiently at room temperature – routinely within minutes – and unimpeded by polar functional groups. No protecting groups, metals, or air-free techniques are required. Regiochemistry can be tuned electronically to explore diverse macrocycle connectivities. Templates with additional reaction capabilities can further manipulate macrocycle structure. The chemistry lays a foundation to extend studies of how the size, shape and constitution of peptidyl macrocycles correlate with their pharmacological properties. |
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