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Optimized Protocol for Synthesis of Cyclic Gramicidin S: Starting Amino Acid Is Key to High Yield

2005; American Chemical Society; Volume: 71; Issue: 1 Linguagem: Inglês

10.1021/jo051519m

1520-6904

Parvesh Wadhwani, Sergii Afonin, Marco Ieronimo, Jochen Buerck, Anne S. Ulrich,

Biochemical and Structural Characterization

A simple and highly efficient Fmoc solid-phase protocol for synthesizing the antimicrobial decapeptide gramicidin S and various labeled analogues is presented. When preparing the linear precursor peptides (1a−e), a systematic permutation of the starting amino acid within the cyclic sequence gave different yields between 51% and 93%. Also the subsequent step of cyclization gave widely diverging yields between 26% and 74%, depending again on the starting amino acid. The ease of cyclization was found to correlate with the tendency of the respective linear precursor peptide to assume a preorganized conformation, as observed by circular dichroism. The overall yield is thus critically dependent on the starting amino acid and can be raised from 20% to 70% using dPhe. The choice of coupling agent and its counterion was found to play only a marginal role. Irrespective of being able to assume a preorganized conformation, none of the linear precursor peptides exhibited any antimicrobial or hemolytic activity. Using the optimized protocol, which involves only simple Fmoc-couplings and requires no intermittent purification steps, several gramicidin S analogues (3−8) containing 19F-labeled phenylglycine derivatives and/or 15N-labeled amino acids were synthesized for solid-state NMR structure analysis.