Development of an integrated strategy to characterize new lead compounds based on natural pro-drugs and their metabolites.

Many natural products are pro-drugs that are metabolized and activated after oral administration. Nevertheless this aspect is usually overlooked when searching for new lead compounds for therapeutic agents. In this project Filipendula ulmaria (meadowsweet) and Herniaria hirsuta have been selected as case studies for the characterization of new leads for anti-inflammatory drugs, and drugs for nephrolithiasis. An LC-MS and 1H-NMR platform will be used for the fast metabolomic profiling of plant extracts, prepared using comprehensive extraction methods to cover the full range of constituents. Secondly, the platform will be extended with a dialysis model simulating human gastro-intestinal (GI) metabolization, which will be applied to activate potential pro-drugs. In addition, the dialysate containing the GI metabolites will be treated with microsomal S9 fractions to mimic liver metabolization. The resulting metabolized samples (before and after S9 treatment) will be profiled in the same LC-MS and 1H-NMR platform, and compared with the original profiles. At the same time all extracts and metabolized extracts will be pharmacologically evaluated in a range of in vitro assays related to anti-inflammatory and anti-nephrolithiasisproperties. Pharmacological and chromatographic / phytochemical data will be analyzed in a metabolomics approach using multivariate data analysis in order to characterize the pharmacologically active constituents and their metabolites as new lead compounds.

Keywords:NATURAL PRODUCTS, PHARMACOGNOSY

Disciplines:Biochemistry and metabolism, Systems biology, Chemical product design and formulation, Biomaterials engineering, Medical biochemistry and metabolism, Biomarker discovery and evaluation, Drug discovery and development, Medicinal products, Pharmaceutics, Pharmacognosy and phytochemistry, Pharmacology, Pharmacotherapy, Toxicology and toxinology, Other pharmaceutical sciences