Partial (alphaMe)Aun scan of [L-Leu(11)-OMe]-trichogin GA IV, a membrane active synthetic precursor of the natural lipopeptaibol

We synthesized using solution-phase methods three analogs of [L-Leu(11)-OMe] trichogin GA IV, a membrane active synthetic precursor of the lipopeptaibol antibiotic in which the N-terminal n-octanoyl group and each of the three Aib residues in positions 1, 4 and 8 are replaced by an acetyl group and the lipophilic C-alpha,C-alpha-disubstituted glycine L-(alpha Me)Aun, respectively [partial (alpha Me)Aun scan]. FT-IR absorption and CD analyses unequivocally show that the main three-dimensional structural features of [L-Leu(11)-OMe] trichogin GA IV are preserved in the analogs. Also, [L-Leu(11)-OMe] trichogin GA IV and the three N-alpha-acetylated L-(alpha Me)Aun analogs exhibit strictly comparable membrane-modifying properties. Taken together, these results strongly favor the conclusion that a shift of the long hydrocarbon moiety from the W-blocking group to the side-chain of the 1, 4 or 8 residue does not have any significant effect on the conformational properties or the membrane activity Of [L-Leu(11)-OMe] tricho-gin GA IV and, by extension, of the natural lipopeptaibol.