Bioactive metabolites from marine invertebrates

Recent results in the chemistry of bioactive marine products are presented. Concerning the cytotoxic a-carbolines : grossularins A and B, the mechanism of the toxicity using supercoiled DNA and synthesis of the imidazolo-a-carboline moiety are presented. In the polysulfur compounds series, the structure of lissoclinotoxin B is proposed as well as a new synthesis of pentathiepins. Novel sesquiterpene sulfates from a Spongiu sp. are described as p8OCdC25 inhibitors. Our program devoted to search of bioactive compounds in marine invertebrates involves two important steps: first, screening of extracts and pure compounds and, second, synthesis of active compounds. Concerning the first point we developed simple tests directed towards specific targets : DNA, enzymes involved in the cell cycle or cause of disorders (Na+/K+ATPase, phospholipase A2, elastase) which offered the advantage of direct elucidation of the mechanism of the activity. We also engaged synthesis of the most active compounds, because availability of a molecule is a perequisite condition for a possible development. Moreover, synthesis may afford interesting analogues. From a tunicate Dendrodoa grossuluriu we previously isolated a series of original indolic derivatives, and among them the grossularines A and B, the first a-carbolines from a natural source. In a cloning system bioassay they proved to be cytotoxic for human solid tumor cells (1,2). ' Q-r& H Grossularin A 1 : R = Grossularin B 2 : R = R Experiments using viscosimetric titration performed on calf thymus DNA and supercoiled DNA @BR 322) showed that helix lenghtening and unwinding angle induced by grossularin B were similar to those provoked by the standard ethydium bromide. The classical intercalators stabilized DNA helix against thermal denaturation; in such an experiment 2. showed a typical bimodal transition behaviour typical reflecting the stabilization induced by this compound. In contrast, grossularin A appeared to be an helix destabilizer (3). Gel electrophoresis separation is an easy method to perform in view to appreciate DNA strand scission (4). Electrophoresis migration of pBR 322 in presence of both grossularins, in presence or absence of CuC12, was performed. We can observe that with grossularine A, in presence of CuC12, 2223