Ascidiacyclamides containing oxazoline and thiazole motifs assume square conformations and show high cytotoxicity

Four cyclic octapeptides were designed from ascidiacyclamide [cyclo(-Ile-Oxz-D-Val- Thz-)2 ] (ASC, 1) to investigate the effects of oxazoline (Oxz) and thiazole (Thz) rings on the structures and cytotoxicities of the peptides. cyclo(-Ile-Thz-D-Val-Oxz-)2 (2) had the same number of Oxz and Thz rings as ASC, but the ring positions were switched. cyclo(-Ile-Oxz-D-Val-Thz-Ile-Thz-D-Val-Thz-) (3) and cyclo(-Ile-Thz-D-Val-Oxz-Ile-Thz-D-Val-Thz-) (4) contained one Oxz and three Thz rings within the molecule. All Oxz rings were substituted with Thz in cyclo(-Ile-Thz-D-Val-Thz-)2 (5). These analogues had new Oxz and Thz blocks forming the 24-membered ring. Based on CD spectra and X-ray diffraction analyses, the structures of all four analogues were classified as square ASC forms. But the structures of 2 and 5 differed from the original square form of 1, and they showed no cytotoxicity. The structure of 3 was very similar to that of 1, and 3 showed 10 times greater cytotoxicity than 1. Although no definite structure of 4 was obtained, it showed three times greater cytotoxicity than 1. It appears that the position and number of Oxz residues are essential determinants in the structure-cytotoxicity relationship of ASC analogues.