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.
Highlights
Marine-derived fungi have proved to be a major source of natural products due to their complex genetic background and chemodiversity [1,2]
Marine sediments represent an unexplored resource for the isolation of fungal strains [3]
Recent studies show that small molecule modulation of the acetyl-lysine binding activity of BRD proteins such as the bromodomain and extra-terminal domain (BET) family protein BRD4 dictates gene transcription outcome in disease models such as lymphoma, ischemia, and human immunodeficiency virus (HIV)-associated kidney disease, indicating BRD4 protein as an attractive drug target for pathologies including cancer and inflammation [9]
Summary
Marine-derived fungi have proved to be a major source of natural products due to their complex genetic background and chemodiversity [1,2]. In the field of drug discovery, epigenetic targets are attracting the attention of more and more researchers Proteins of this kind of targets are mainly classified into readers, writers, and erasers of marks on histones, DNA, or other nuclear proteins [5]. Recent studies show that small molecule modulation of the acetyl-lysine binding activity of BRD proteins such as the bromodomain and extra-terminal domain (BET) family protein BRD4 dictates gene transcription outcome in disease models such as lymphoma, ischemia, and HIV-associated kidney disease, indicating BRD4 protein as an attractive drug target for pathologies including cancer and inflammation [9]. In order to explore new BRD4 inhibitors and lead compounds for the development of new from marine natural products, the secondary metabolites of Alternaria sp. BRD4 inhibitor which may make a contribution to drug discovery
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
