ISOLATION OF DOLASTATINS 10-15 FROM THE MARINE MOLLUSK DOLABELLA-AURICULARIA

A twenty year pursuit of the cell growth inhibitory and antineoplastic constituents of the Western Indian Ocean (Mauritius) sea hare Dolabella auricularia has resulted in the discovery of fifteen structurally unique peptide, cyclopeptide, depsipeptide, and cyclodepsipeptide type-substances designated dolastatins 1-15. Solution of the difficult isolation problems leading to discovery of dolastatins 10-15 in 10(-6) to 10(-7)% yields required 1,600 kg of Dolabella auricularia. To date, this represents the largest scale separation of sea hare components. Of these dolastatin 10 (4) has displayed unprecedented potency in experimental antineoplastic and tubulin assembly systems. Dolastatin 15 (9), and to a lesser extent dolastatin 14 (8) were also found to exhibit unusually strong antineoplastic activity. Both dolastatins 10 and 15 are in advanced preclinical development. Details of the isolation strategies and structural summaries for dolastatins 10-15 have been recorded.