UC Santa Cruz
Selective, On-Resin N-Methylation of Cyclic Peptides and Implications for the Discovery of Membrane Permeable Scaffolds
- Author(s): White, Tina Renea
- Advisor(s): Scott, William G.
- et al.
Many biologically active cyclic peptides, especially those of natural origin, are known to penetrate cells by passive diffusion despite lying well outside Lipinski's "rules of 5" for predicting bioavailability. The backbone amides of these natural products are often N-methylated, a modification that serves to enhance lipophilicity and proteolytic stability. The impact of N-methylation on passive membrane diffusion in cyclic peptides, however, has not been investigated in detail. Here we present a new method for the selective, on-resin N-methylation of cyclic peptides to generate compounds with drug-like membrane permeability. The selectivity and degree of N-methylation of the cyclic peptide depends on the stereochemistry of the backbone, suggesting that conformation dictates the regiochemistry of the N-methylation reaction. For two of the diastereomers investigated, unique N-methyl products were observed with each diastereomer yielding a different N-methyl variant. 2D 1H NMR and H/D exchange studies provide insight into the conformational basis of the regioselectivity of the reaction and provide a rationale for the observation that the partially methylated derivatives are not only significantly more membrane permeable than their nonmethylated precursors, but are also more permeable than the corresponding permethylated species.