Dolastatin H and Isodolastatin H, Potent Cytotoxic Peptides from the Sea Hare Dolabella auricularia: Isolation, Stereostructures, and Synthesis

A bioassay-directed investigation of the cytotoxic constituents of the Japanese sea hare Dolabella auricularia resulted in the isolation of two cytotoxic compounds designated dolastatin H ( 2 ) and isodolastatin H ( 3 ) from the wet animals at the yields of 9 × 10 -7 %. On the basis of spectroscopic analysis, these compounds were shown to be new peptides that were closely related to dolastatin 10 ( 1 ) isolated from Western Indian Ocean specimens of this animal. The notable structural feature of these new compounds, 2 and 3, is that 3-phenylpropane-1,2-diol is attached through the ester linkage to the C-terminus of a tetrapeptide containing unusual amino acids. The absolute stereostructures of 2 and 3 were unambiguously determined by enantioselective total synthesis. A cytotoxicity test for synthetic 2, 3, and their C-2 epimers revealed that the stereochemistry of the 3-phenylpropane-1,2-diol moiety on the C-terminus plays an important role in their cytotoxicity. In vivo antitumor activity against murine P388 leukemia was evaluated, and it was shown that isodolastatin H ( 3 ) exhibited antitumor activity a little weaker than that of dolastatin 10 ( 1 ).