代谢物分析
药物发现
代谢物
天然产物
计算生物学
注释
仿形(计算机编程)
化学
生物
生物化学
生物信息学
计算机科学
操作系统
作者
Tanja Hell,Adriano Rutz,Lara Dürr,Maciej Dobrzyński,Jakob K. Reinhardt,Timo Lehner,Morris Keller,Anika John,Mahabir P. Gupta,Olivier Pertz,Matthias Hamburger,Jean‐Luc Wolfender,Eliane Garo
标识
DOI:10.1021/acs.jnatprod.2c00146
摘要
The discovery of bioactive natural products remains a time-consuming and challenging task. The ability to link high-confidence metabolite annotations in crude extracts with activity would be highly beneficial to the drug discovery process. To address this challenge, HPLC-based activity profiling and advanced UHPLC-HRMS/MS metabolite profiling for annotation were combined to leverage the information obtained from both approaches on a crude extract scaled down to the submilligram level. This strategy was applied to a subset of an extract library screening aiming to identify natural products inhibiting oncogenic signaling in melanoma. Advanced annotation and data organization enabled the identification of compounds that were likely responsible for the activity in the extracts. These compounds belonged to two different natural product scaffolds, namely, brevipolides from a Hyptis brevipes extract and methoxylated flavonoids identified in three different extracts of Hyptis and Artemisia spp. Targeted isolation of these prioritized compounds led to five brevipolides and seven methoxylated flavonoids. Brevipolide A (1) and 6-methoxytricin (9) were the most potent compounds from each chemical class and displayed AKT activity inhibition with an IC50 of 17.6 ± 1.6 and 4.9 ± 0.2 μM, respectively.
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