Strategies for the Optimization of Natural Leads to Anticancer Drugs or Drug Candidates

Abstract Natural products have made significant contribution to cancer chemotherapy over the past decades and remain an indispensable source of molecular and mechanistic diversity for anticancer drug discovery. More often than not, natural products may serve as leads for further drug development rather than as effective anticancer drugs by themselves. Generally, optimization of natural leads into anticancer drugs or drug candidates should not only address drug efficacy, but also improve absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles and chemical accessibility associated with the natural leads. Optimization strategies involve direct chemical manipulation of functional groups, structure–activity relationship directed optimization and pharmacophore‐oriented molecular design based on the natural templates. Both fundamental medicinal chemistry principles (e.g., bioisosterism) and state‐of‐the‐art computer‐aided drug design techniques (e.g., structure‐based design) can be applied to facilitate optimization efforts. In this review, the strategies to optimize natural leads to anticancer drugs or drug candidates are illustrated with examples and described according to their purposes. Furthermore, successful case studies on lead optimization of bioactive compounds performed in the Natural Products Research Laboratories at UNC are highlighted.