ABSTRACT
A wide range of toxins with interesting pharmacological properties have been isolated from ascidians. These include cyclic peptides, one of which, didemnin B, is undergoing clinical trials for cancer chemotherapy and is also a powerful immunosuppressive agent. Other classes of toxins from these organisms are alkaloids, macrolides, polyethers, prenylated hydroquinones and others of diverse chemical structure. The majority of these compounds are cytotoxic and in some cases the mechanisms of action have been investigated. The toxins are most likely used for chemical defense but the question of how the ascidians themselves escape the toxic actions is also not resolved.
Subject(s)
Acetamides , Marine Toxins/chemistry , Pyrans , Alkaloids/chemistry , Amino Acid Sequence , Animals , Carotenoids/chemistry , Ethers, Cyclic/chemistry , Molecular Sequence Data , Peptides, Cyclic/chemistry , Spiro Compounds , UrochordataABSTRACT
Two new lissoclinamides (lissoclinamides 7 and 8) have been isolated from the aplousobranch ascidian Lissoclinum patella. These lissoclinamides are cyclic heptapeptides with the same structural features as lissoclinamides 4 and 5 reported earlier, containing an oxazoline ring, one proline, one valine, two phenylalanine residues, and thiazole and/or thiazoline rings. All four peptides have the same sequence of amino acids around the ring and differ from one another only in their stereochemistry or the number of thiazole and thiazoline rings. The cytotoxicities of the compounds were tested with human fibroblast and bladder carcinoma cell lines and normal lymphocytes. Slight changes in structure resulted in marked differences in the cytotoxicities of these compounds. The most potent is lissoclinamide 7, containing two thiazoline rings, which rivals didemnin B in cytotoxicity in vitro.
Subject(s)
Cell Survival/drug effects , Peptides, Cyclic/isolation & purification , Urochordata , Animals , Magnetic Resonance Spectroscopy , Peptides, Cyclic/pharmacology , Protein Conformation , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
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.
