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Communication

Testing the Conformational Hypothesis of Passive Membrane Permeability Using Synthetic Cyclic Peptide Diastereomers

Supporting Info

Taha Rezai,^† Bin Yu,^† Glenn L. Millhauser,^† Matthew P. Jacobson,^‡ and R. Scott Lokey*^†

Department of Chemistry and Biochemistry, University of California, Santa Cruz, 1156 High Street, Santa Cruz, California 95064, and Department of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, San Francisco, California 94143-2442

J. Am. Chem. Soc., 2006, 128 (8), pp 2510–2511

DOI: 10.1021/ja0563455

Publication Date (Web): February 4, 2006

†

University of California, Santa Cruz.

‡

University of California, San Francisco.

In papers with more than one author, the asterisk indicates the name of the author to whom inquiries about the paper should be addressed.

, lokey@chemistry.ucsc.edu

Abstract

Little is known about the effect of conformation on passive membrane diffusion rates in small molecules. Evidence suggests that intramolecular hydrogen bonding may play a role by reducing the energetic cost of desolvating hydrogen bond donors, especially amide N−H groups. We set out to test this hypothesis by investigating the passive membrane diffusion characteristics of a series of cyclic peptide diastereomers based on the sequence cyclo[Leu-Leu-Leu-Leu-Pro-Tyr]. We identified two cyclic hexapeptide diastereomers based on this sequence, whose membrane diffusion rates differed by nearly two log units. Results of solution NMR studies and hydrogen/deuterium (H/D) exchange experiments showed that membrane diffusion rates correlated with the degree of intramolecular hydrogen bonding and H/D exchange rates. The most permeable diastereomer, cyclo[d-Leu-d-Leu-Leu-d-Leu-Pro-Tyr] (1), exhibited a passive membrane diffusion rate comparable to that of the orally available drug cyclosporine A.

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