Identification and characterization of reactive metabolites in natural products-driven drug discovery

Toxicity of natural products arising from their metabolic biotransformation into reactive chemical intermediates is an important reason for high attrition rates in early drug discovery efforts. Screening promising natural products for their likelihood to form such metabolites is therefore an important step in identifying potential liabilities in the drug development process. However, such screening is complicated by the need to have test methods that are sensitive, reliable, accurate, efficient, and cost-effective enough to allow for routine identification and characterization of the reactive metabolites. These metabolites are typically formed in minute quantities, usually through minor metabolic pathways, and, due to their highly reactive and therefore transient chemical nature, pose considerable analytical challenges in attempts to determine their properties. Understanding the formation of reactive metabolites may be used as the basis for synthetic chemical modification of parent natural products aimed at bypassing such harmful bioactivation. This paper highlights the general principles and protocols commonly used to predict and study the formation of reactive metabolites in vitro and how the data obtained from such studies can be used in the development of safer drugs from natural products.