Natural products (NPs) represent a unique source of chemical diversity that exhibit a wide variety of biological activities. Exploring and designing diverse compound collections using unique and under-utilized NPs as scaffolds for medicinal chemistry studies increases the chances of discovering new chemical probes and/or future leads that could be developed into new drugs.1
This project is significant as it applies knowledge from synthetic, medicinal and combinatorial chemistry to novel NP-scaffolds that results in the creation of small (10–20 analogues) but unique discovery libraries. This study will allow for the exploration of unique chemical space and provide distinct screening libraries containing potential drug, lead or probe molecules.
Two NP scaffolds, valerenic acid (1) and gibberellic acid (2), have recently been modified to generate libraries of analogues via parallel solution-phase synthesis.2,3 The library based on 1 was screened for anti-inflammatory activity. 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.2 The gibberellic acid library was evaluated for in vitro cytotoxicity and deregulation of lipid metabolism in human prostate cancer cells (LNCaP). While no cytotoxic activity was identified at the concentrations tested, five semi-synthetic analogues substantially reduced cellular uptake of free cholesterol in LNCaP cells, suggesting a novel role of gibberellic acid derivatives in deregulating cholesterol metabolism.3
(1) Barnes, E. C. et al. Nat. Prod. Rep. 2016; 33: 372-381
(2) Egbewande, F. A. et al. Bioorg. Med. Chem. Lett. 2017; 27: 3185-3189
(3) Egbewande, F. A. et al. J. Nat. Prod. 2018; DOI: 10.1021/acs.jnatprod.7b00929