International Union of Pure and Applied Chemistry

Structural studies of marine peptides*

Annette M. Fernandez,¹ Hai-yin He,^2,3 Leonard A. McDonald,^1,3 Piotr Lassota,³ Carolyn Discafani,³ Erik F. Sorensen,³ Michael C. Edler,¹ Louis R. Barrows,¹ Jon C. Clardy^2* and Chris M. Ireland¹1. Departments of Medicinal Chemistry and Pharmacology and Toxicology, University of Utah, Salt Lake City, UT 84112
2. Department of Chemistry, Cornell University, Ithaca, NY 14853-1301
3. Wyeth Ayerst Research, Pearl River, NY 10965
Email: [email protected]

Abstract: Previous studies in my lab and others have shown that the didemnid ascidians are a rich source of bioactive peptides, many of which contain cysteine. These cysteine residues in the form of disulfide bridges or five membered heterocyclic rings seem to constrain the peptides to specific conformations. Extracts of the colonial marine ascidian Didemnum cucculiferum collected at Beqa lagoon in the Fiji Islands showed potent cytotoxicity in a 25 cell line panel of human solid tumors and activity in a cell based assay for detection of tubulin polymerization inhibitors. Fractionation of the extract yielded a new cyclic peptide vitilevuamide, which contains the monosulfur bridge amino acid lanthionine. The structure of vitilevuamide was determined using NMR and mass spectrometry. Vitilevuamide inhibits polymerization of tubulin dimers to microtubules at 2 m M. It inhibits binding of vinblastine to tubulin in a non-competitive manner and has little effect on GTP or dolastatin 10 binding.

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