Unusual Spirodecane Sesquiterpenes and a Fumagillol Analogue from <i>Cordyceps ophioglossoides</i>

Sun, Yisheng; Zhao, Zhao; Qi, Feng; Xu, Qinqin; Lü, Longxian; Liu, Ji‐Kai; Zhang, Ling; Wu, Bin; Li, Yongquan

doi:10.1002/hlca.201200068

Cited by 20 publications

(11 citation statements)

References 28 publications

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“…Compounds 6 and 9 were identified as 6-demethoxyfumagillol 23 and cordycol, 24 respectively, based on MS and NMR comparison to standards. 9 is the monoepoxide relative of 6 and may therefore be an immediate precursor of 6 .…”

Section: Resultsmentioning

confidence: 99%

Generation of Complexity in Fungal Terpene Biosynthesis: Discovery of a Multifunctional Cytochrome P450 in the Fumagillin Pathway

Lin¹,

Tsunematsu

Dhingra

et al. 2014

J. Am. Chem. Soc.

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Fumagillin (1), a meroterpenoid from Aspergillus fumigatus, is known for its antiangiogenic activity due to binding to human methionine aminopeptidase 2. 1 has a highly oxygenated structure containing a penta-substituted cyclohexane that is generated by oxidative cleavage of the bicyclic sesquiterpene β-trans-bergamotene. The chemical nature, order, and biochemical mechanism of all the oxygenative tailoring reactions has remained enigmatic despite the identification of the biosynthetic gene cluster and the use of targeted-gene deletion experiments. Here, we report the identification and characterization of three oxygenases from the fumagillin biosynthetic pathway, including a multifunctional cytochrome P450 monooxygenase, a hydroxylating nonheme-iron-dependent dioxygenase, and an ABM family monooxygenase for oxidative cleavage of the polyketide moiety. Most significantly, the P450 monooxygenase is shown to catalyze successive hydroxylation, bicyclic ring-opening, and two epoxidations that generate the sesquiterpenoid core skeleton of 1. We also characterized a truncated polyketide synthase with a ketoreductase function that controls the configuration at C-5 of hydroxylated intermediates.

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Section: Resultsmentioning

confidence: 99%

Generation of Complexity in Fungal Terpene Biosynthesis: Discovery of a Multifunctional Cytochrome P450 in the Fumagillin Pathway

Lin¹,

Tsunematsu

Dhingra

et al. 2014

J. Am. Chem. Soc.

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“…Cordycepol C could also inhibit Hep3B cells (p53-deficient) proliferation with an IC 50 value (24 h) of 42.4 µg/mL and Huh-7 cells (p53 mutant) with the IC 50 value of 43.4 µg/mL by MTT assays (Fig. 5A), while these data were less variant compared with the IC 50 value in HepG2 cells (37.9 µg/mL) or SMMC-7721 (42.1 µg/mL) 24) (Fig. 2F).…”

Section: Cordycepol C Induces the Loss Of δψ M And Mitochondrial Tranmentioning

confidence: 89%

“…24) A stock solution of 20 mg/mL cordycepol C was prepared in dimethyl sulfoxide (DMSO) and diluted to the appropriate concentrations before use; the final concentration of DMSO was kept below 0. Cell Viability Assay The cell viability was measured by the MTT method as previously described.…”

Section: Cell Culture and Reagentsmentioning

confidence: 99%

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Cordycepol C Induces Caspase-Independent Apoptosis in Human Hepatocellular Carcinoma HepG2 Cells

Sun

Zhao

et al. 2014

Biological & Pharmaceutical Bulletin

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Cordycepol C, a novel sesquiterpene isolated from the cultured mycelia of Cordyceps ophioglossoides, contains a hydroperoxy group and is cytotoxic to HepG2 cells. So far, no sesquiterpenes have been found in the genus Cordyceps and it would be interesting to investigate the antitumor efficacy as well as the mechanism of action of this unusual sesquiterpene. In this study, we showed that cordycepol C induced apoptosis of the HepG2 cells without affecting the normal liver cell line L-02. Cordycepol C caused poly(ADP-ribose) polymerase-1 (PARP-1) cleavage and triggered the loss of mitochondrial membrane potential (Δψ m ) in HepG2 cells in a time-and dose-dependent manner, resulting in the nuclear translocation of apoptosis-inducing factor (AIF) and endonuclease G (Endo G). We also found that cordycepol C induced the expression of Bax protein, followed by its translocation from the cytosol to mitochondria in both wild type and p53 knockdown HepG2 cells. However, cordycepol C could not cause cleavages of procaspase-3, -8, and -9. Caspase activities were not increased and Z-VAD-fmk, a caspase inhibitor, could not prevent the apoptosis induced by cordycepol C. These findings indicate that cordycepol C induces caspase-independent apoptosis in HepG2 cells through a p53-independent and Bax-mediated mitochondrial pathway, leading to the nuclear translocation of AIF and Endo G. Our study provides the molecular mechanism by which cordycepol C induces apoptosis in hepatocellular carcinoma cells and indicates the potential use of cordycepol C as an antitumor agent.

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“…Cordycepol C and cordycol ( Table 2) concentration-and time-dependently reduced the number of carcinoma cells, with relatively low effect on normal liver LO 2 cell line. Results imply that these two molecules may be promising lead compounds in treating human hepatic carcinoma [72].…”

Section: Sesquiterpenesmentioning

confidence: 94%

Mycotherapy of Cancer: An Update on Cytotoxic and Antitumor Activities of Mushrooms, Bioactive Principles and Molecular Mechanisms of their Action

Popović¹,

Živković²,

Davidović³

et al. 2013

CTMC

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Mycotherapy is defined as the study of the use of extracts and compounds obtained from mushrooms as medicines or health-promoting agents. The present review updates the recent findings on anticancer/antitumor agents derived from mushroom extracts and their metabolites. The increasing number of studies in the past few years revealed mushroom extracts as potent antitumor agents. Also, numerous studies were conducted on bioactive compounds isolated from mushrooms reporting the heteropolysaccharides, β-glucans, α-glucans, proteins, complexes of polysaccharides with proteins, fatty acids, nucleoside antagonists, terpenoids, sesquiterpenes, lanostanoids, sterols and phenolic acids as promising antitumor agents. Also, molecular mechanisms of cytotoxicity against different cancer cell lines are discussed in this review. Findings with Antrodia camphorata and Ganoderma lucidium extracts and isolated compounds are presented, as being the most deeply studied previously.

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Unusual Spirodecane Sesquiterpenes and a Fumagillol Analogue from Cordyceps ophioglossoides

Cited by 20 publications

References 28 publications

Generation of Complexity in Fungal Terpene Biosynthesis: Discovery of a Multifunctional Cytochrome P450 in the Fumagillin Pathway

Generation of Complexity in Fungal Terpene Biosynthesis: Discovery of a Multifunctional Cytochrome P450 in the Fumagillin Pathway

Cordycepol C Induces Caspase-Independent Apoptosis in Human Hepatocellular Carcinoma HepG2 Cells

Mycotherapy of Cancer: An Update on Cytotoxic and Antitumor Activities of Mushrooms, Bioactive Principles and Molecular Mechanisms of their Action

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