Conformational restraints induced by modification of configuration of threonine and oxazoline residues in ascidiacyclamide analogues: Threonine and oxazoline residues in ascidiacyclamide analogues

After designing the desoxazoline-ascidiacyclamide diastereomers cyclo(-Ile-Thr-D-Val-thiazole-)(2) (3) and cyclo(-Ile-D-allo-Thr-D-Val-thiazole-)(2) (5), the molecules were treated with thionyl chloride treatments to yield the ascidiacyclamide diastereomers cyclo(-Ile-allo-oxazoline-D-Val-thiazole-)(2) (4) and cyclo(-Ile-D-oxazoline-D-Val-thiazole-)(2) (6). X-ray diffraction analyses revealed the folded forms of 3 and 5 and the square form of 4. The structure of 6 was a novel reverse-square form, and the CD spectra suggested the structures of 4 and 6 differ in solution. Whereas trifluoroethanol titration showed 4 to be conformationally flexible, 6 was comparatively rigid. The cytotoxicity of 4 was similar to that of ascidiacyclamide, but 3, 5 and 6 was not cytotoxic. Together with earlier studies, these results suggest that the conformational flexibility of ascidiacyclamide is important for its cytotoxicity.