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. 2017 Mar 16;15(3):76.
doi: 10.3390/md15030076.

Inhibitors of BRD4 Protein from a Marine-Derived Fungus Alternaria sp. NH-F6

Affiliations

Inhibitors of BRD4 Protein from a Marine-Derived Fungus Alternaria sp. NH-F6

Hui Ding et al. Mar Drugs. .

Abstract

Bromodomains (BRD) are readers of the epigenetic code that regulate gene transcription through their recognition of acetyl-lysine modified histone tails. Recently, bromodomain-containing proteins such as BRD4 have been demonstrated to be druggable through the discovery of potent inhibitors. These protein-protein interaction inhibitors have the potential to modulate multiple diseases by their profound anti-inflammatory and antiproliferative effects. In order to explore new BRD4 inhibitors as well as lead compounds for the development of new drugs, the secondary metabolites of Alternaria sp. NH-F6, a fungus isolated from deep-sea sediment samples, were analyzed systematically. Five new compounds including two new perylenequinones (1-2), one new alternaric acid (3), 2-(N-vinylacetamide)-4-hydroxymethyl-3-ene-butyrolactone (4), one new cerebroside (5), together with 19 known compounds (6-24) were isolated from the ethyl acetate extracts of this strain. Their structures were elucidated using nuclear magnetic resonance (NMR) and high resolution electrospray ionization mass spectrometry (HR-ESI-MS) analyses. Finally, all these compounds were evaluated for their inhibitory activity against BRD4 protein, and compound 2 exhibited a potent inhibition rate of 88.1% at a concentration of 10 µM. This research provides a new BRD4 inhibitor which may possess potential antitumoral, antiviral, or anti-inflammatory pharmaceutical values.

Keywords: Alternaria sp. NH-F6; marine-derived fungus; secondary metabolites.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structures of compounds 124.
Figure 2
Figure 2
Key HMBC (formula image), 1H-1H COSY (formula image) and NOESY (formula image) correlations of compound 1.
Figure 3
Figure 3
Key HMBC (formula image), 1H-1H COSY (formula image) and NOESY (formula image) correlations of compound 2.
Figure 4
Figure 4
Key HMBC (formula image) and 1H-1H COSY (formula image) correlations of compound 3.
Figure 5
Figure 5
Key HMBC (formula image) and 1H-1H COSY (formula image) correlations of compound 4.
Figure 6
Figure 6
Key HMBC (formula image) and 1H-1H COSY (formula image) correlations of compound 5.

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