The isolation and structures of a new patellamide (patellamide D) and two new lissoclinamides (lissoclinamides 4 and 5) from the aplousobranch ascidian Lissoclinum patella are described. Structures were determined largely by using two-dimensional NMR techniques and mass spectrometry. These peptides and other members of the patellamide and lissoclinamide families that have been reported previously are found within the obligate algal symbiont of the genus Prochloron. The cytotoxicities of the compounds toward fibroblast and tumor cell lines are reported. One of these compounds, lissoclinamide 4, is markedly more toxic than other members of the family. Structure-activity relationships are discussed.

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A comparison of a closely related set of cyclic octapeptides demonstrates how Nature has adapted two common amino acid building blocks (Thr, Cys) as conformational ring constraints (oxazoline, thiazole) to regulate the three-dimensional structures and reactivities of marine macrocycles. A 2D NMR spectroscopic study shows that conversion of two Cys residues in the flexible cyclic octapeptide 1, c[Ile-Thr-d-Val-Cys-Ile-Thr-d-Val-Cys-], to 5-membered thiazole rings (Thz) leads to the formation of a novel pseudochair conformation in 2, c[Ile-Thr-d-(Val)Thz-Ile-Thr-d-(Val)Thz-]. The conformational flexibility of 2 is significantly restricted by three intramolecular hydrogen bonds induced by the d-(Val)Thz components, resulting in a single solution conformation with non-C 2 symmetric side chains. Additional modification, through conversion of the two threonine side chains to 5-membered oxazoline rings (Oxn), produces a highly constrained pseudoboat or saddle-shaped macrocycle, c[(Ile)Oxn-d-(Val)Thz-(Ile)Oxn-d-(Val)Thz-] (7), having C 2 symmetric side chains. Acid hydrolysis of 7, previously isolated from the ascidian Lissoclinum patella, selectively opens the two oxazoline rings with further conformational rearrangement to a novel cyclic octapeptide (8) possessing a shallower pseudoboat conformation. The comparison reveals that oxazoline and thiazole rings impose severe conformational restrictions upon these cyclic octapeptides, creating unusual shapes and clefts with varying capacities to capture organic or metal ion guests (e.g. 10). Such dramatic changes in macrocycle shape may be related to the differential antitumour and metal-binding properties of this class of molecule.

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