Nitrobenzoyl Sesquiterpenoids with Cytotoxic Activities from a Marine-Derived <i>Aspergillus ochraceus</i> Fungus

Background and Purpose: Osteoclasts are unique cells to absorb bone. Targeting osteoclast differentiation is a therapeutic strategy for osteolytic diseases. Natural marine products have already become important sources of new drugs. The naturally occurring nitrobenzoyl sesquiterpenoids first identified from marine fungi in 1998 are bioactive compounds with a special structure, but their pharmacological functions are largely unknown. Here, we investigated six marine fungus-derived nitrobenzoyl sesquiterpenoids on osteoclastogenesis and elucidated the mechanisms. Experimental Approach: Compounds were first tested by RANKL-induced NF-κB luciferase activity and osteoclastic TRAP assay, followed by molecular docking to characterize the structure-activity relationship. The effects and mechanisms of the most potent nitrobenzoyl sesquiterpenoid on RANKL-induced osteoclastogenesis and bone resorption were further evaluated in vitro. Micro-CT and histology analysis were used to assess the prevention of bone destruction by nitrobenzoyl sesquiterpenoids in vivo. Key Results: Nitrobenzoyl sesquiterpenoid 4, with a nitrobenzoyl moiety at C-14 and a hydroxyl group at C-9, was the most active compound on NF-κB activity and osteoclastogenesis. Consequently, nitrobenzoyl sesquiterpenoid 4 exhibited suppression of RANKL-induced osteoclastogenesis and bone resorption from 0.5 μM. It blocked RANKL-induced IκBa phosphorylation, NF-κB p65 and RelB nuclear translocation, NFATc1 activation, reduced DC-STAMP but not c-Fos expression during osteoclastogenesis in vitro. Nitrobenzoyl sesquiterpenoid 4 also ameliorated LPSinduced osteolysis in vivo. Conclusion and Implications: These results highlighted nitrobenzoyl sesquiterpenoid 4 as a novel inhibitor of osteoclast differentiation. This marine-derived sesquiterpenoid is a promising lead compound for the treatment of osteolytic diseases.

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“…The extraction process and structures of nitrobenzoyl sesquiterpenoids were described in our previous study (Tan et al, 2018).…”

Section: Reagents and Antibodiesmentioning

confidence: 99%

A marine fungus‐derived nitrobenzoyl sesquiterpenoid suppresses receptor activator of NF‐κB ligand‐induced osteoclastogenesis and inflammatory bone destruction

Tan

Deng

Zhang

et al. 2020

British J Pharmacology

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“…Compounds 14-O-acetylinsulicolide A (31), 6β,9α-dihydroxy-14-p-nitrobenzoylcinnamolide (29) and insulicolide A (30) (Figure 1) displayed activities with IC 50 values of 0.89 to 8.20 µM. Further studies indicated that compound 31 arrested the cell cycle at the G0/G1 phase at a concentration of 1 µM and induced late apoptosis at a concentration of 2.00 µM after a 72-h treatment of 786-O cells [41]. Therefore, the nitrobenzoyl sesquiterpenoids have attracted attention of researchers, because of their good antitumor potential.…”

Section: Terpenoidsmentioning

confidence: 99%

“…Compounds 29 and 30 displayed significant cytotoxicity against 10 human cancer cell lines, with IC 50 values of 1.95 to 6.35 µM [40]. There are few nitrobenzoyl sesquiterpenoids reported in the literature, most of them being obtained from fungi of the genus Aspergillus of marine origin that were isolated from sediment [73], and from marine organisms such as seaweed [40,41,72] and sponges [73].…”

Section: Terpenoidsmentioning

confidence: 99%

Antitumor Potential of Seaweed Derived-Endophytic Fungi

et al. 2019

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The marine environment presents a high biodiversity and a valuable source of bioactive compounds with therapeutic and biotechnological potential. Among the organisms present in marine environment, the endophytic fungi isolated from seaweed stand out. These microorganisms have aroused interest in the scientific community regarding its various activities such as antiviral, antimicrobial, antioxidant, photoprotective, cytotoxic, genotoxic, anti-inflammatory, and anticancer, besides establishing important ecological relations with its hosts. Anticancer molecules derived from marine natural sources are a promising target against different types of cancer. The disease’s high rates of morbidity and mortality affect millions of people world wild and the search for new therapeutic alternatives is needed. Thus, this review partially summarizes the methodologies for the isolation of seaweed-derived endophytic fungi, as well as describes the anticancer compounds isolated from such microorganisms, reported in the literature from 2009 to the present. In addition, it describes how some biotechnological processes can help in the discovery of bioactive compounds, especially with anticancer activity.

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“…Marine-derived fungi are reported as a prodigious source of development for new antivirals against different important viruses (Moghadamtousi et al, 2015 ). In our continuing endeavor to discover biologically active compounds from marine microbes, a series of structurally interesting and biologically active natural products have been described (Luo et al, 2017 ; Tan et al, 2018 ). Recently, six new cytotoxic chloroazaphilone derivatives, isochromophilones A–F, have been isolated from the fungus Diaporthe sp.…”

Section: Introductionmentioning

confidence: 99%

Structurally Diverse Polyketides From the Mangrove-Derived Fungus Diaporthe sp. SCSIO 41011 With Their Anti-influenza A Virus Activities

et al. 2018

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Influenza A virus (IAV) is a severe worldwide threat to public health and economic development due to its high morbidity and mortality. Marine-derived fungi have been evidenced as a prolific source for the discovery of pharmacologically-active lead compounds. During the course of our search for novel bioactive substances from marine microorganisms, six new polyketides, including two octaketides (1–2), one chromone derivative (13), two highly substituted phthalides (17–18), and one α-pyrone derivative (21) along with 22 known congeners were isolated from a mangrove-associated fungus Diaporthe sp. SCSIO 41011. Their structures were determined by spectroscopic analysis and by comparison with literature data. And the absolute configurations were established according to the specific rotation or electron circular dichroism method. Antiviral evaluation results revealed that compounds 14, 15, 26, and 5-chloroisorotiorin displayed significant anti-IAV activities against three influenza A virus subtypes, including A/Puerto Rico/8/34 H274Y (H1N1), A/FM-1/1/47 (H1N1), and A/Aichi/2/68 (H3N2), with IC50 values in the range of 2.52–39.97 μM. The preliminary structure-activity relationships (SARs) are also discussed. These findings expand the chemical and bioactive diversity of polyketides derived from the genus Diaporthe, and also provide a basis for further development and utilization of chromone, xanthone, and chloroazaphilone derivatives as source of potential anti-viral chemotherapy agents.

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Nitrobenzoyl Sesquiterpenoids with Cytotoxic Activities from a Marine-Derived Aspergillus ochraceus Fungus

Cited by 53 publications

References 12 publications

A marine fungus‐derived nitrobenzoyl sesquiterpenoid suppresses receptor activator of NF‐κB ligand‐induced osteoclastogenesis and inflammatory bone destruction

A marine fungus‐derived nitrobenzoyl sesquiterpenoid suppresses receptor activator of NF‐κB ligand‐induced osteoclastogenesis and inflammatory bone destruction

Antitumor Potential of Seaweed Derived-Endophytic Fungi

Structurally Diverse Polyketides From the Mangrove-Derived Fungus Diaporthe sp. SCSIO 41011 With Their Anti-influenza A Virus Activities

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