[Modification of natural products for drug discovery].

Pharmacological activity and druggability are two essential factors for drug innovation. The pharmacological activity is definitely indispensable, and the druggability is destined by physico-chemical, biochemical, pharmacokinetic and safety properties of drugs. As secondary metabolites of animals, plants, microbes and marine organisms, natural products play key roles in their physiological homeostasis, self-defense, and propagation. Natural products are a rich source of therapeutic drugs. As compared to synthetic molecules, natural products are unusually featured by structural diversity and complexity more stereogenic centers and fewer nitrogen or halogen atoms. Naturally active substances usually are good lead compounds, but unlikely meet the demands for druggability. Therefore, it is necessary to modify and optimize these structural phenotypes. Structural modification of natural products is intent to (1) realize total synthesis ready for industrialization, (2) protect environment and resources, (3) perform chemical manipulation according to the molecular size and complexity of natural products, (4) acquire novel structures through structure-activity relationship analysis, pharmacophore definition, and scaffold hopping, and (5) eliminate unnecessary chiral centers while retain the bioactive configuration and conformation. The strategy for structural modification is to increase potency and selectivity, improve physico-chemical, biochemical and pharmacokinetic properties, eliminate or reduce side effects, and attain intellectual properties. This review elucidates the essence of natural products-based drug discovery with some successful examples.