天然产物的结构改造

药理活性和成药性是新药创制的两大要素, 药理活性自不待言, 成药性是由分子的物理化学性质、生物化学性质、药代动力学性质和安全性所支撑。天然产物作为动物、植物、微生物和海洋生物的次级代谢产物, 具有维持生理、自身防御和种群繁衍的功能, 许多药物来自天然产物。天然产物具有多样性和复杂性结构, 多含立体化学中心, 氮和卤素含量低。天然活性物质是良好的先导物, 但未必能满足成药性要求, 需要进行结构修饰和优化。结构改造的要旨是: 根据天然产物的分子大小和复杂程度, 采取不同的化学处置方式, 复杂和较大的分子作结构剖裂, 去除冗余原子; 研究构效关系, 提取药效团, 实现骨架迁越, 获得新结构类型分子; 消除不必要的手性中心, 保留与靶标结合的必须的构型与构象; 全合成实现工业化, 保护环境与资源。天然产物结构改造的方略是: 提高活性强度和选择性作用; 改善物理化学性质; 提高化学和代谢稳定性; 改善生物化学性质; 改善药代动力学性质; 消除或降低毒副作用和不良反应; 获得知识产权。本文以成功的实例解析以天然活性物质为先导物研制新药的内涵。

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.