Conformational studies and structure-activity analysis of lissoclinamide 7 and related cyclopeptide alkaloids

The macrocyclic arrays of heterocycles and amides present in Lissoclinum peptides can serve as templates for selective metal ion binding and as lead structures for the design of conformationally preorganized peptides and peptidomimetics. The currently available secondary structure information for this class of marine alkaloids, however, is limited to 18- and 24-membered ring isomers. This work provides the first information on the solid state and solution conformation of the 21-membered class of Lissoclinum cyclopeptide alkaloids. The folding of lissoclinamide 7, both in the solid and in the solution state, is dominated by a combination of a type II beta-turn formed at the prolyloxazoline moiety and a beta-loop segment stabilized by intramolecular five-membered hydrogen bonds at the thiazoline-D-phenylalanine-thiazoline moiety. The resulting rigid backbone geometry controls the preferred stereochemistry at the stereogenic alpha-carbons, and the natural compound represents the thermodynamically most favorable stereoisomer. In addition to these structural studies, we have compared the relative cytotoxicity of lissoclinamide 7 with analogues with selective oxazoline and thiazoline heterocycle replacements. On the basis of in vitro cell toxicity assays, we can conclude that the substitution of thiazolines in the natural product with oxazoline rings leads to a general decrease in cellular toxicity. However, changes in the stereochemistry of the parent macrocycle also influence cytotoxicity.