An integrated strategy to characterize new anti-inflammatory lead compounds derived from Filipendula ulmaria (meadowsweet)

Since many NSAID show severe gastrointestinal side effects, there is a high need for new drugs. [1] An integrated strategy, based on natural pro-drugs and their metabolites, is developed to characterize new anti-inflammatory lead compounds derived from Filipendula ulmaria.

Firstly, the phytochemical composition was explored in a comprehensive manner using UPLC-DAD-HRMS. Next to salicylates like salicylic acid, an active in vivo metabolite, a rich diversity of phenolic constituents was identified. [2],[3]

Extensive biotransformation after oral intake can be expected. This urges the need for identification and activity profiling of the intestinal and hepatic metabolites. Therefore, an in vitro gastrointestinal biotransformation model (GIBM) was used, which mimics the gastric, intestinal and colonic phase, including fecal fermentation. [4] These metabolites subsequently undergo in vitro hepatic biotransformation via human S9 fraction. Salicin, an inactive pro-drug in F. ulmaria, was tested as proof-of-concept: a time-dependent hydrolysis of salicin to saligenin in the GIBM was observed. Saligenin was further biotransformed to salicylic acid by the S9 fraction.

As a last step, biotransformed samples will be evaluated with in vitro anti-inflammatory assays, focusing on cyclooxygenase (COX). [5] A non-biotransformed extract of F. ulmaria (20 µg/mL) was tested in a cell-based COX-2 gene expression assay. No inhibition was observed. However, the same extract (50 µg/mL) showed an inhibition of 76.6 ± 2.4% on the COX-1 and 43.7 ± 9.9% on the COX-2 enzyme.

The combination of these analytical and in vitro methods, results in an innovative concept to identify and further develop new leads for drugs.

• References

• 1 Brune K, Patrignani P. New insights into the use of currently available non-steroidal anti-inflammatory drugs. J Pain Res 2015; 8: 105-118
• 2 Bijttebier S, Van der Auwera A, Voorspoels S, Noten B, Hermans N, Pieters L. , et al. A First Step in the Quest for the Active Constituents in Filipendula ulmaria (Meadowsweet): Comprehensive Phytochemical Identification by Liquid Chromatography Coupled to Quadrupole-Orbitrap Mass Spectrometry. Planta Med 2016; 82 (06) : 559-572
• 3 Bijttebier S, Van der Auwera A, Foubert K, Voorspoels S, Pieters L, Apers S. Bridging the gap between comprehensive extraction protocols in plant metabolomics studies and method validation. Anal Chim Acta 2016; 935: 136-150
• 4 Breynaert A, Bosscher D, Kahnt A, Claeys M, Cos P, Pieters L. et al. Development and validation of an in vitro experimental gastrointestinal dialysis model with colon phase to study the availability and colonic metabolisation of polyphenolic compounds. Planta Med 2015; 81: 1075-1083
• 5 Katanić J, Boroja T, Mihailović V, Nikles S, Pan SP, Rosić G. et al. In vitro and in vivo assessment of meadowsweet (Filipendula ulmaria) as anti-inflammatory agent. J Ethnopharmacol 2016; 193: 627-636