Organic & Biomolecular Chemistry
Communication
the follow-up in vivo biological study of eryvarin H and its ana-
logues due to their limited potential as a selective ERRγ
inverse agonist. Even though this study failed to produce a
selective and potent inverse agonist of ERRγ, this study clearly
exemplified the rational drug discovery procedure using in
silico docking simulation with a collection of natural products,
followed by total synthesis of a natural product and its ana-
logues as a potential perturbagen of proteins-of-interest. We
envision that this rational approach can be adapted to identify
a new small molecule that modulates the function of new
therapeutic targets and key signaling pathways.
This work was supported by the Bio & Medical Technology
Development Program (2012M3A9C4048780), a Global Frontier
Project Grant (2011-0032150), the WCU Program (R31-10032),
the Basic Research Laboratory (2010-0019766), and a National
Creative Research Initiatives Grant (20110018305 to H.-S.C.)
funded by the National Research Foundation of Korea (NRF).
J.Y.K. and M.K. are grateful for a BK21 Scholarship and a Seoul
Science Fellowship.
Fig. 4 Transcriptional activities of eryvarin H, 11, and 12 towards other NRs: (a)
ERα, (b) mCAR, (c) HNF4 and (d) SF-1. Normalized luciferase activities of each NR
were tested in HEK-293. T cells upon treatment of three compounds to test their
selective inverse agonism over that in ERRγ. E2 refers to estradiol.
over ERα. However, the efficacy and specificity of eryvarin H we
observed in this study are not comparable to those of GSK5182
that we have used for the biochemical studies of ERRγ.
References
In conclusion, natural products have been serving as essen-
tial perturbagens in various biological processes due to their
evolutional heritage and structural diversity. As a continuation
of our effort at the functional modification of ERRγ, we aimed
to develop a novel ERRγ inverse agonist via in silico docking
analysis with a collection of natural products. The computer-
aided ligand discovery allowed the identification of eryvarin H
(1) as a potential inverse agonist of ERRγ. Along with a limited
supply of eryvarin H via extraction from natural resources, the
inability for a structure–activity relationship of this natural
product against ERRγ led us to pursue the first total synthesis
of eryvarin H and its structural analogues. In addition, we
wanted to decipher the molecular basis of its interaction with
residues at the ligand binding pocket of ERRγ, which has high
structural similarity and sequence homology with ERα. There-
fore, we prepared two key intermediates, vinyl bromides (2a)
and arylboronic ester (3), and successfully completed the total
synthesis of eryvarin H through Pd-mediated Suzuki–Miyaura
cross-coupling of two intermediates in reasonable overall
yields. With this modular synthetic route, we also prepared 12
derivatives (8–19) of eryvarin H simply by changing the substi-
tuents on arylboronic esters or introducing a dimethyl substi-
tuent at the C-2 position of TBS-protected 3-bromo-2H-
chromen-7-ol. The resulting 13 analogues including eryvarin H
were subjected to the cell-based reporter gene assay using DNA
plasmid containing Gal4-fused ERRγ LBD to measure their
biological activity as ERRγ inverse agonists. Among these
derivatives, eryvarin H and compound 12 showed meaningful
ERRγ inverse agonistic activities along with moderate selec-
tivity over ERα and other NRs. However, the level of efficacy
and specificity of eryvarin H toward ERRγ over ERα is not com-
parable to that of GSK5182 that we have used for the biochemi-
cal studies of ERRγ. Therefore, we unfortunately discontinued
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