Construction and Biological Evaluation of Small Libraries Based on the Intermediates within the Total Synthesis of Uvaretin

摘要

Natural products(NPs)have played a vital role in the treatment of diseases， and are the cornerstone for modern drug discovery， since 2600 B.C.in which oils from Cupressus semperviren and Commiphora were used in the treatment of coughs， colds， and inflammation.[1] From individual therapeutic agent discovery to inspiration for the construction of non-natural bioactive agents， their impact is immeasurable.[2] While NPs constituted the major pipeline for therapeutic agent discovery for decades， the introduction of high-throughput screening(HTS)in the late 1980s allowed for the discovery of drug lead scaffolds via chemical screening libraries(CSLs);initially solely populated by NPs， NP fragments， and NPs analogs.[3] To answer the call for the population of CSL in a rapid fashion the industry turned towards the use of sp2-sp2 metal catalyzed coupling reactions to gain access to tens to hundreds of thousands of small molecules for HTS， as means of identifying new drug lead scaffolds.[4] While numerous FDA approved drugs have been discovered in this fashion， these compounds tend to lack in the chemical diversity， complexity， and inherent biological activity of natural products.[4] To address the diversity of CSLs， multiple research programs have undertaken various approaches to construct new CSLs that either possess structural complexity， rapid small-molecule construction， biological activity-based design， and others.[5] All of these approaches， as expected， have their pros and cons associated with them.Noting the historical importance of NPs， the development of CSLs based upon NPs should deliver CSLs with not only biological activity， but chemical diversity in terms of structural complexity， biological modulating properties， and rich physicochemical properties.