The present research proposal is designed to test the hypothesis that marine organism-derived natural products can provide clinically useful pharmaceutical agents. Specifically, antitumor agents will be sought, and to a lesser degree antimicrobial, antiviral, and immunosuppressive agents. These represent multiple goals of which the antitumor target is the most readily accessible and is now in sight. Research will focus on ecteinascidin 743 (ET 743) and dehydrodidemnin B (Aplidine). These two compounds from our laboratory are now in clinical trial in Europe and North America as anticancer agents. ET 743, from the tunicate (sea squirt) Ecteinascidia turbinata, currently in Phase II clinical trials, is present in only 1 g/ton of the tunicate and efforts will be made to increase the quantity available for human testing by defining the biosynthetic pathway, including precursors and intermediates. Attempts will be made to establish whether a symbiotic microorganism may actually produce ET 743. More active derivatives and analogs of ET743 will be sought and developed. Oxidative degradation will be studied to characterize the metabolites and perhaps to slow drug degradation in patients. Aplidine (dehydrodidemnin B) is currently in Phase I trials and may be regarded as a second-generation analog of didemnin B (DB). The latter reached Phase II trials and showed promise in treating non-Hodgkins lymphoma but was dropped due to cardiac toxicity. By contrast Aplidine is up to 30 times as active as DB and lacks its cardiotoxicity. Biosynthesis of Aplidine and DB will be studied in Spain and the Caribbean, respectively, but is complicated by its symbiotic relationship with the cyanobacterium Synechocystis trididemniii, which will be studied separately. Ring opened analogs of Aplidine and DB will be prepared to see whether they represent biosynthetic intermediates or degradation products of the cyclic depsipeptide. Amide analogs of the Hip and Thr units will also be prepared, to stabilize the cyclic depsipeptides and hinder in vivo hydrolysis. A cyanobacterial product, a mixture of oscillacidins A and B from an Oscillatoria species, appears to be toxic to L1210 leukemia cells and is being investigated for its unique structure, different from the hepatotoxins microcystins and nodularin, which are cyclic heptapeptides and pentapeptides containing the novel acid Adda.
