TAWICYCLAMIDES-A AND TAWICYCLAMIDES-B, NEW CYCLIC-PEPTIDES FROM THE ASCIDIAN LISSOCLINUM-PATELLA - STUDIES ON THE SOLUTION-STATE AND SOLID-STATE CONFORMATIONS

Two new cytotoxic cyclic peptides, tawicyclamides A and B (1-2), were isolated from the ascidian Lissoclinum patella collected in the Philippine Islands and their structures determined by NMR spectroscopy, oxidation studies, and tandem mass spectrometry. Absolute configurations were determined by HPLC analysis of derivatized constituent amino acids obtained from acid hydrolysis. X-ray crystallography confirmed the structure of tawicylamide B and showed that the compound assumes an unusual conformation facilitated by a cis-valine-praline amide bond and stabilized by an intramolecular hydrogen bond. Tawicyclamides A and B represent a new family of cyclic octapeptides, possessing thiazole and thiazoline amino acids but lacking the oxazoline ring characteristic of previously reported cyclic peptides from L. patella. Isomerization of the valine-proline amide bond from cis to trans is among the conformational changes occurring upon oxidation of the thiazoline ring to a thiazole. A variety of NMR data supports these changes. Molecular modeling studies allowed us to establish the solution conformations of these compounds and to evaluate these conformational interpretations. Tawicyclamides A and B were weakly but equally cytotoxic against human colon tumor cells in vitro.