Drug Discovery from Natural Sources

A discussion of the role of natural products as drugs and/or following partial or complete chemical synthesis, have been approved human use drugs in at least one country, or alternatively is/are the source of inspiration for further investigation. The blister beetle toxin pederin and the multiple structurally similar natural products from marine sources demonstrated that this base structure is microbial in origin and therefore may be manipulated. Subsequent investigations led to significant discoveries as to the actual source(s) of many nominal bioactive sponge metabolites. The microbial origin of the dolastatins and their derivatives as warheads in ADCs with at least four entities being approved and may be more in the clinical pipeline. The total syntheses of vancomycins have now produced agents that have overcome the microbial resistance phenotypes. Possibilities from chemical modifications of the anthracyclines may lead to novel ADC-like constructs. The 20-year synthetic chemistry program to generate bioactive modifications of the halichondrins led to the totally synthetic antitumor agent (eribulin) and a novel fully synthetic halichondrin B analog plus an ADC based on eribulin. Both are now in phase I clinical trials in Japan. I discussed artemisinin and its current derivatives as antimalarial, antiviral, and potential antitumor agents. Recognizing that most bioactive natural product structures from marine sources are predominately microbial in origin (even if not yet fermentable), when coupled to excellent synthetic chemistry applications, has opened up drug discovery and subsequent development in previously unexpected ways. These advances have led to the application of genomics particularly utilizing discoveries in microbial sources, with the proven ability to fully characterize the genome (from a single cell) of as yet unculturable microbes and to utilize the skill sets of synthetic chemists to modify these bioactive precursors.