An integrated strategy to characterize new anti-inflammatory lead compounds derived from **Filipendula ulmaria** (meadowsweet)
The scope of this PhD thesis was to develop an integrated strategy, based on natural pro-drugs and their metabolites, to characterize new anti-inflammatory lead compounds derived from Filipendula ulmaria. The plant is widely used in phytotherapy against inflammatory diseases. However, its active constituents are not exactly known. It contains many constituents, such as flavonoid glycosides, which are not absorbed. However, these compounds are metabolized in the colon by gut microbiota, producing potentially active metabolites that can be absorbed. The aim of this study was to characterize the active constituents or metabolites. As a first step, the phytochemical composition of F. ulmaria was explored in a comprehensive manner. A rich diversity of phenolic constituents was (tentatively) identified via UHPLC-PDA-amMS. In total, 119 compounds were tentatively identified, of which 69 compounds were not reported before in F. ulmaria. In view of the phenolic nature of the main constituents, extensive biotransformation after oral intake before absorption can be expected. This urges the need for identification and activity profiling of the intestinal metabolites. Therefore, as a second step, the comprehensive extract was subjected to in vitro gastrointestinal biotransformation, which mimics the gastric, intestinal and colonic phase, including fecal fermentation in an anaerobic environment. Samples before, during and after biotransformation were analyzed with UHPLC-ESI-QTOF-MS. To tackle the dynamic and complex nature of this data, an in house automated data analysis workflow for multiclass longitudinal data was used to screen interesting biotransformation profiles in an unbiased manner. Lastly, in vitro anti-inflammatory activity was evaluated by testing the inhibition of NF-κB activation, COX-1 and COX-2 enzyme inhibition. The simulation of gastrointestinal biotransformation showed a decrease in the relative abundance of glycosylated flavonoids such as rutin, spiraeoside and isoquercitrin in the colon compartment, and an increase in aglycons such as quercetin, apigenin, naringenin and kaempferol. The non-biotransformed extract showed significant inhibitory activity in NF-κB. The genuine as well as the metabolized extract showed a better inhibition of the COX-1 enzyme as compared to COX-2. A mix of aglycons present after biotransformation showed a significant inhibition of COX-1. The activity may be explained by an additive or synergistic effect of genuine constituents and metabolites. To conclude, this new integrated approach offers added value to medicinal plant research, allowing phytochemical identification of compounds and their metabolites after in vitro biotransformation, followed by preliminary in vitro activity testing, omitting time consuming and expensive in vivo studies in early stages of research.
Antwerpen : Universiteit Antwerpen, Faculteit Farmaceutische, Biomedische en Diergeneeskundige Wetenschappen, Departement Farmaceutische Wetenschappen , 2023
XIV, 293 p.
Supervisor: Pieters, L. [Supervisor]
Supervisor: Hermans, N. [Supervisor]
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Creation 22.09.2023
Last edited 15.10.2023
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