Partial [alpha Me]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 lipopeptaib ol antibiotic in which the N-terminal n-octanoyl group and each of the thre e 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, respe ctively [partial (alpha Me)Aun scan]. FT-IR absorption and CD analyses uneq uivocally show that the main three-dimensional structural features of [L-Le u(11)-OMe] trichogin GA IV are preserved in the analogs. Also, [L-Leu(11)-O Me] trichogin GA IV and the three N-alpha-acetylated L-(alpha Me)Aun analog s exhibit strictly comparable membrane-modifying properties. Taken together , these results strongly favor the conclusion that a shift of the long hydr ocarbon 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 propert ies or the membrane activity Of [L-Leu(11)-OMe] tricho-gin GA IV and, by ex tension, of the natural lipopeptaibol.