CONFORMATIONAL STUDIES AND STRUCTURE-ACTIVITY ANALYSIS OF LISSOCLINAMIDE-7 AND RELATED CYCLOPEPTIDE ALKALOIDS

The macrocyclic arrays of heterocycles and amides present in Lissoclin um peptides can serve as templates for selective metal ion binding and as lead structures for the design of conformationally preorganized pe ptides and peptidomimetics. The currently available secondary structur e information for this class of marine alkaloids, however, is limited to 18- and 24-membered ring isomers. This work provides the first info rmation on the solid state and solution conformation of the 21-membere d class of Lissoclinum cyclopeptide alkaloids. The folding of lissocli namide 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 mo iety and a beta-loop segment stabilized by intramolecular five-membere d hydrogen bonds at the thiazoline-D-phenylalanine-thiazoline moiety. The resulting rigid backbone geometry controls the preferred stereoche mistry at the stereogenic alpha-carbons, and the natural compound repr esents the thermodynamically most favorable stereoisomer. In addition to these structural studies, we have compared the relative cytotoxicit y of lissoclinamide 7 with analogues with selective oxazoline and thia zoline heterocycle replacements. On the basis of in vitro cell toxicit y assays, we can conclude that the substitution of thiazolines in the natural product with oxazoline rings leads to a general decrease in ce llular toxicity. However, changes in the stereochemistry of the parent macrocycle also influence cytotoxicity.