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

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.

Secondary Metabolites with Nitric Oxide Inhibition from Marine-Derived Fungus Alternaria sp. 5102

“…Finally, compound 1 was crystallized upon slow evaporation of chloroform solvent to give a crystal of the monoclinic space group P2 1 , which was detected by X-ray crystallography. The refinement of the Cu Kα data resulted in a Flack parameter [18] of 0.04 (17) and a Hooft parameter [19] of 0.07 (5), which assigned the absolute configuration of 1 as 3S, 10S, and 11S ( Figure 3). The absolute configuration of secondary alcohol was further resolved by a modified Mosher's method [20,21].…”

“…Chemical investigation of an extract of marine-derived fungus Alternaria sp. 5102 from rice medium led to the discovery of two new benzofurans, alternabenzofurans A and B (1 and 2) and two new sesquiterpenoids, alternaterpenoids A and B (3 and 4), along with 18 known polyketides (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Their structures were clearly elucidated by extensive spectroscopic analyses and X-ray crystallography, as well as the modified Mosher's method.…”

“…Marine-derived fungi are a significant source of pharmacological molecules with interesting and diversified structural properties [1][2][3][4]. Among them, the fungal genus Alternaria had a widespread distribution in marine source [4] (including sediment [5], sponge [6], alga [7], mangrove [8], soft coral [9]) and could produce plenty of structural molecules, including nitrogen-containing compounds, steroids, terpenoids, pyranones, quinones, and phenolics [10]. These metabolites exhibited a variety of biological activities such as cytotoxic, antimicrobial, enzyme inhibitor properties [10].…”

Glycosylated Natural Products From Marine Microbes

“…In order to explore bromodomains (BRD) inhibitors, the secondary metabolites of Alternaria sp. NH-F6, a fungus obtained from deep-sea sediment samples, were analyzed and led to a cerebroside (166, Figure 12) along with two perylenequinones (Ding et al, 2017). Under continuous searching for bioactive natural products from Red-Sea marine-derived fungi, the fungus Penicillium was isolated from the tunicate Didemnum and led to two cerebrosides, penicillosides A-B (167-168, Figure 12).…”

Novel Natural Products from Extremophilic Fungi

“…NH-F6 (depth 3927 m, the South China Sea). Compound 111 was a potent inhibitor with an inhibition rate of 88.1% at 10 μM, while 110 had a moderate inhibition at rate of 57.7% at the same concentration [ 44 ].…”