Natural products (NPs) represent a unique source of chemical and structural diversity that exhibit a wide variety of biological activities. Exploring and designing diverse compound collections using unique and under-utilized NP scaffolds increases the chances of discovering chemical probes and/or future leads that could be developed into new drugs. This project is significant as it combines knowledge from synthetic and combinatorial chemistry, and uses novel NP-templates to create smaller and smarter libraries. This study will allow for the exploration of unique chemical space and provide distinctive screening libraries containing potential drug, lead or probe molecules. To date, three unique scaffolds, valerenic acid, gibberellic acid, and thiaplakortone A have been modified to generate libraries of analogues via parallel solution-phase synthesis. The library based on the valerenic acid scaffold has recently been screened for anti-inflammatory activity at LEO Pharma’s Open Innovation platform. This library was tested in two separate anti-inflammatory in vitro assays based on IL-8 and TNF-α inhibition. Six analogues showed moderate inhibitory activity in the IL-8 assay with IC50 values of 2.8–8.3 μM, while none of the tested compounds showed any significant effect on inhibiting TNF-α release. The gibberellic acid library is undergoing high-throughput screening for anti-cancer activity against several promising targets in prostate cancer that are linked to oxidative stress, redox homeostasis, lipid metabolism and mitochondrial function; all these processes are critical for prostate cancer growth and survival. The small library based on thiaplakortone A is currently being synthesized and will be evaluated for anti-malarial activity.

Generation of natural products-based screening libraries for drug discovery

254th National Meeting (2017)

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