Structural Simplification of Natural Products

Natural products (NPs) are important sources of clinical drugs due to their structural diversity and biological prevalidation. However, the structural complexity of NPs leads to synthetic difficulties, unfavorable pharmacokinetic profiles, and poor drug-likeness. Structural simplification by truncating unnecessary substructures is a powerful strategy for overcoming these limitations and improving the efficiency and success rate of NP-based drug development. Herein, we will provide a comprehensive review of the structural simplification of NPs with a focus on design strategies, case studies, and new technologies. In particular, a number of successful examples leading to marketed drugs or drug candidates will be discussed in detail to illustrate how structural simplification is applied in lead optimization of NPs.