Design and Synthesis of Natural Product-Based Screening Libraries

Abstract

Natural products (NPs) continue to have significant impact in the area of drug discovery and development. More than 50% of the approved drugs between 1981 and 2014 were either unaltered NPs, NP derivatives or synthetic drugs inspired by NP pharmacophores. NPs have also served as lead molecules in drug development programs; noteworthy example include the semi-synthetic antifungal drugs caspofungin, anidulafungin, and micafungin that were based on NP lead compounds isolated from the fermentation products of various fungus. Other notable examples include the sponge metabolite halichondrin B that was developed into the anticancer drug eribulin, and camptothecin, a plant NP that was developed into the oncology drugs, topotecan and irinotecan. Many research groups are now utilizing isolated NPs as scaffolds for the generation of semi-synthetic analogue libraries rather than pursuing the total synthesis of a bioactive NP followed by classic medicinal chemistry. This approaches main advantage is the reduction in timelines and resource allocation, which is typically associated with de novo multi-step syntheses of a bioactive NP. Furthermore, once the NP scaffold has been isolated from the source biota rapid analogue generation and subsequent SAR data can be acquired. Thus the evaluation of a scaffold chemotype for potential lead optimization studies is quickly assessed.