Philippe Bouchet

Onchidin: a cytotoxic depsipeptide with C2 symmetry from a marine mollusc

Onchidin (1) is a cytotoxic depsipcptide isolatcd from thc pulmonate mollusc Onchidium sp. Its structure is cyclo (MeVal-Amo-Val-Hiv-Hiv-McVal-Amo-Val-Hiv-Hiv) made or two identical halves (C3OH49N307, MeVal-Amo-Val-Hiv-Hiv). Onchidin contains a new s-amino acid: 3-amino-2-methyl- oct-7-ynoic acid (Amo). It has C2-symmetry and this makcs one half homotopic to the other so only signals for a monomer can be seen in the NMR spectra. Thc structure and absolute stereochemistry (all S) of onchidin was determined by extcnsivc spcctroscopic analysis, selective hydrolysis and chiral GCMS. Cyclic peptides with important pharmacological properties have been isolated from manne 0rganisms.l Frequently these metabolites contain D amino acids, hydroxy acids, new a-amino acids, new s-amino acids and thiazole and oxazole rings. In some cases, the cyclic structure incorporates elements of symmetry that complicate the structural determination due to the bonding possib es of the repeating fragments and the simplification of the spectra. The interest of these compounds is well illustrated by dolastatin- IO, the most potent antineoplastic agent known2 and by the didemnins,3 considered as some of the most promising antitumor compounds of marine origin. In this paper we describe the structure (including absolute configuration) of onchidin (1) a new cytoxic depsipeptide with C2 symmetry isolated from a pulmonate mollusc known to be a rich source of y- pyrone poIypropionates4. Onchidium sp. (Pulmonatu, order: Sryfommarophora) (3Kg. fresh weight) collected off New Caledonia was extracted with methanol. P-388 and Kb activity-guided fractioning by solvent partition followed by repeated chromatography (Sephadex, reverse phase HPLC) afforded 3 mg of a pure compound ((a)&=-140.9; P-388

σ Values of N-substituted azoles

The σp coefficients of azoles and their benzo-derivatives have been determined by i.r. and n.m.r. spectroscopy, based on the study of the NH2 bands arising from 1-p-aminophenylazoles.