S107: Meeting the Supply Needs of Marine Cyanobacterial Drug Leads through Synthesis and Metabolic Engineering

Marine cyanobacteria are an extraordinarily rich source of novel bioactive secondary metabolites. One such derivative, brentuximab vedotin, is now used as a clinical anticancer agent, and many others have shown potential for the treatment of cancer, inflammation, pain, and other diseases. However, a general impediment to the development of many of these exciting molecules is the limited quantities obtained from Nature as well as the difficulty in culturing the source organisms. In some cases, total chemical synthesis of natural metabolites and analogs is possible.  In others, the producing strain can be adapted to laboratory culture and provide a reasonable supply.  Finally, in still other cases, it can be attractive to harness the biosynthetic assembly system to provide for re-supply. In this presentation, all of these approaches will be given example from isolated and structurally characterized metabolites from our laboratory.  In the synthetic arena, our group has produced the natural products as well as analogs of the honaucins which have antiinflammatory properties, and the carmaphycins which are cancer cell cytotoxic yet stimulatory to neuritogenesis.  We have scaled-up the laboratory culture of several filamentous marine cyanobacteria so as to produce 100 mg quantities of desired natural products, such as curacin A and hectochlorin. In the heterologous expression area, we have been involved along with others in efforts to clone and heterologously overexpress biologically active cyanobacterial metabolites.  These examples indicate that advances are being made in several different ways to meet the ‘supply needs’ for biologically active natural products.