Natural Products: Back to the Future in Drug Discovery

Nature offers an endless pool of unique molecular frameworks with desirable drug-like properties, rendering them ideal starting points for the development of pharmaceuticals [1]. In fact, the history of natural products (NPs) in drug discovery has been extraordinarily successful over the past century, highlighted by prominent examples as the antitumor agents taxol, vinblastine or doxorubicin, the immunosuppressant’s for organ transplants cyclosporine and rapamycin, or the cholesterollowering agents statins, the top-selling drugs today. Despite this glorious past, trends in pharmaceutical industry moved in the early 90’s towards high-throughput screening (HTS) of synthetic compound libraries, coinciding with the premiere of Back to the Future, the science-fiction adventure film directed by Robert Zemeckis and starred by Michael J. Fox ($380 million worldwide in a year) [2]. Owing to the continual pressure within the market to find ‘blockbuster drugs’ and dazzled by the novel breakneck assay speed of combinatorial synthetic chemistry, most of firms cut back their programs of natural product drug discovery. The main argument against doing further screening of natural sources was related to the incompatibility with HTS analysis, based on issues such as 1) high structural complexity which slows the identification process and makes challenging further chemical modifications, 2) slow production of the target compound into a complex extract which demands labor-intensive purification steps, 3) lack of efficient dereplication methodologies which leads in some cases to rediscovery known compounds.