Combining activity profiling with advanced annotation to accelerate the discovery of natural products targeting oncogenic signaling in melanoma

Hell, Tanja and Rutz, Adriano and Dürr, Lara and Dobrzyński, Maciej and Reinhardt, Jakob K. and Lehner, Timo and Keller, Morris and John, Anika and Gupta, Mahabir and Pertz, Olivier and Hamburger, Matthias and Wolfender, Jean-Luc and Garo, Eliane (2022) Combining activity profiling with advanced annotation to accelerate the discovery of natural products targeting oncogenic signaling in melanoma. Journal of Natural Products, 85 (6). pp. 1540-1554.

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Abstract

The discovery of bioactive natural products remains a time-consuming and challenging task. The ability to link highconfidence 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 UHPLCHRMS/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.

Item Type:	Article
Subjects:	R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) R Medicine > RM Therapeutics. Pharmacology
Depositing User:	Fergie Pineda
Date Deposited:	01 Nov 2023 15:17
Last Modified:	01 Nov 2023 15:17
URI:	http://up-rid.up.ac.pa/id/eprint/6902

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