Department of Chemistry and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch, 7701, South Africa.
J Nat Prod. 2012 Mar 23;75(3):507-13. doi: 10.1021/np200786j. Epub 2012 Feb 1.
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.
天然产物代谢生物转化为反应性化学中间体所产生的毒性是早期药物发现工作中高淘汰率的一个重要原因。因此，筛选有希望的天然产物是否有可能形成此类代谢物，是确定药物开发过程中潜在风险的重要步骤。然而，这种筛选受到需要有足够灵敏、可靠、准确、高效和具有成本效益的测试方法的限制，以便能够常规识别和表征反应性代谢物。这些代谢物通常以微量形成，通常通过次要代谢途径，并且由于其高度反应性和因此短暂的化学性质，在试图确定其性质时带来了相当大的分析挑战。了解反应性代谢物的形成可以作为对天然产物母体进行合成化学修饰的基础，旨在避免这种有害的生物活化。本文重点介绍了用于预测和研究体外反应性代谢物形成的一般原则和方案，以及如何在从天然产物开发更安全药物的过程中使用此类研究获得的数据。
