Meroterpenoids from <i>Neosetophoma</i> sp.: A Dioxa[4.3.3]propellane Ring System, Potent Cytotoxicity, and Prolific Expression

El‐Elimat, Tamam; Raja, Huzefa A.; Ayers, Sloan; Kurina, Steven J.; Burdette, Joanna E.; Mattes, Zachary; Sabatelle, Robert C.; Bacon, Jeffrey W.; Colby, Aaron H.; Grinstaff, Mark W.; Pearce, Cedric J.; Oberlies, Nicholas H.

doi:10.1021/acs.orglett.8b03769

Cited by 47 publications

(68 citation statements)

References 18 publications

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“…Tr opolone sesquiterpenoids (TS) are fungal meroterpenoid natural products [1] that display as ignificant array of biological activities.F or example:p ycnidione 1 is an antiproliferative vs.h uman lung cancer cells (9 nM); [2] xenovulene A 2 inhibits the human g-aminobutyrate A( GABA A ) benzodiazepine receptor (40 nM); [3] eupenifeldin 3 and neosetophome B 4 are potent antitumor agents (nanomolar activity towards human cancer cell lines); [1,4] while epolone A 5 selectively induces erythropoietin (EPO) expression in human cells in the mMrange;(Scheme 1A). [5] All tropolone sesquiterpenoids share the structural motif of ac ore 11-membered macrocycle (derived from humulene 6;S cheme 1B)c onnected to one or two dihydropyran rings that link the macrocycle with polyketide-derived tropolones.…”

Section: Introductionmentioning

confidence: 99%

Synthetic Biology Driven Biosynthesis of Unnatural Tropolone Sesquiterpenoids

Schotte

Wibberg

et al. 2020

Angew Chem Int Ed

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Tropolone sesquiterpenoids (TS) are an intriguing family of biologically active fungal meroterpenoids that arise through a unique intermolecular hetero Diels–Alder (hDA) reaction between humulene and tropolones. Here, we report on the combinatorial biosynthesis of a series of unprecedented analogs of the TS pycnidione 1 and xenovulene A 2. In a systematic synthetic biology driven approach, we recombined genes from three TS biosynthetic gene clusters (pycnidione 1, xenovulene A 2 and eupenifeldin 3) in the fungal host Aspergillus oryzae NSAR1. Rational design of the reconstituted pathways granted control over the number of hDA reactions taking place, the chemical nature of the fused polyketide moiety (tropolono‐ vs. monobenzo‐pyranyl) and the degree of hydroxylation. Formation of unexpected monobenzopyranyl sesquiterpenoids was investigated using isotope‐feeding studies to reveal a new and highly unusual oxidative ring contraction rearrangement.

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Section: Introductionmentioning

confidence: 99%

Synthetic Biology Driven Biosynthesis of Unnatural Tropolone Sesquiterpenoids

Schotte

Wibberg

et al. 2020

Angew Chem Int Ed

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“…[5] Die Analyse der COSY-u nd HMBC-Daten für 17 identifizierte das Kohlenstoffgerüst der Humulen-, Tr opolon-und Monobenzopyranyl-Einheiten (ergänzende Abbildung S66-S73 und ergänzende Tabelle S18). Zentrale HMBC/COSY-Korrelationen zwischen H 2 -9' und C-6' sowie zwischen H-9' und H-1 platzierten den Tr opolonring an die Westseite von Humulen; 1 [7] In jedem Genom wurde ein einzelner aspks1-ähnlicher BGC entdeckt (hier als eup2 BGC [CF-150626] und pyc BGC [CF-236968] bezeichnet;A bbildung 2A). Das Artemis-Tool wurde verwendet, um Homologien zwischen den beiden Clustern und dem aspks1 BGC aus A. strictum zu visualisieren (Abbildung 2A).…”

Section: Ergebnisse Und Diskussionunclassified

“…Tr opolon-Sesquiterpenoide (TS) sind pilzliche Meroterpenoide, [1] die eine erhebliche Anzahl biologischer Aktivitäten aufweisen. Zum Beispiel:P ycnidione 1 wirkt antiproliferativ gegen menschliche Lungenkrebszellen (9 nM); [2] Xenovulene A 2 hemmt den menschlichen GABA A -Benzodiazepinrezeptor (40 nM); [3] Eupenifeldin 3 und Neosetophome B 4 sind potente Antitumormittel (nM Aktivitätg egenüber menschlichen Krebszelllinien); [1,4] Epolone A 5 induziert selektiv die Expression von Erythropoetin (EPO) in menschlichen Zellen im mM-Bereich (Schema 1A). [5] Alle Tr opolon-Sesquiterpenoide teilen das Strukturmotiv eines zentralen 11-gliedrigen Makrocyclus (abgeleitet von Humulen 6;S chema 1B), der mit einem oder zwei Dihydropyranringen verbunden ist, die den Makrocyclus mit von Polyketiden abgeleiteten Tr opolonen verbinden.…”

Section: Introductionunclassified

“…B. Epolone A 5. [1,[14][15][16][17] Wirh aben uns füre inen synthetisch biologisch gesteuerten Ansatz zur kombinatorischen/heterologen Biosynthese entschieden, um den chemischen Raum um TS-Naturstoffe rational zu erweitern und zentrale Biosyntheseschritte zu beleuchten. Aspergillus oryzae wurde zuvor als ausgezeichneter Wirt fürd ie Expression von biosynthetischen Genclustern etabliert.…”

Section: Introductionunclassified

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Synthetisch biologisch getriebene Biosynthese von unnatürlichen Tropolon‐Sesquiterpenoiden

Schotte

Wibberg

et al. 2020

Angewandte Chemie

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Tropolon‐Sesquiterpenoide (TS) sind eine faszinierende Familie biologisch aktiver pilzlicher Meroterpenoide, die durch eine einzigartige intermolekulare Hetero‐Diels‐Alder (hDA)‐Reaktion zwischen Humulen und Tropolonen entstehen. Hier berichten wir über die kombinatorische Biosynthese einer Reihe beispielloser Analoga von Pycnidione 1 und Xenovulene A 2. In einem systematischen auf synthetischer Biologie basierendem Ansatz haben wir Gene aus drei Biosynthesegenclustern (Pycnidione 1, Xenovulene A 2 und Eupenifeldin 3) im pilzlichen Wirt Aspergillus oryzae NSAR1 rekombiniert. Das rationale Design der rekonstituierten Biosynthesewege ermöglichte die Kontrolle über die Anzahl der stattfindenden hDA‐Reaktionen, die chemische Natur der kondensierten Polyketideinheit (Tropolono‐ vs. Monobenzopyranyl) und den Hydroxylierungsgrad. Die Bildung unerwarteter Monobenzopyranylsesquiterpenoide wurde mithilfe von Isotopenfütterungsstudien untersucht und führte zur Entdeckung einer neuen und höchst ungewöhnlichen oxidativen Ringkontraktion.

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“…Examples of anticancer drugs that are in use and derived from natural sources include actinomycin D, mitomycin C, bleomycin, etoposide, paclitaxel, docetaxel, and vincristine [5]. Fungal secondary metabolites have gained a lot attention as a source of novel cytotoxic scaffolds [4,7]. Current data estimates as many as 5 million species of fungi growing on earth, of which only a small percentage were studied for bioactive compounds, and an even smaller percentage has been explored for anticancer activity [8].…”

Section: Introductionmentioning

confidence: 99%

Greensporone A, a Fungal Secondary Metabolite Suppressed Constitutively Activated AKT via ROS Generation and Induced Apoptosis in Leukemic Cell Lines

et al. 2019

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Greensporone A is a fungal secondary metabolite that has exhibited potential in vitro for anti-proliferative activity in vitro. We studied the anticancer activity of greensporone A in a panel of leukemic cell lines. Greensporone A-mediated inhibition of proliferation is found to be associated with the induction of apoptotic cell death. Greensporone A treatment of leukemic cells causes inactivation of constitutively activated AKT and its downstream targets, including members GSK3 and FOXO1, and causes downregulation of antiapoptotic genes such as Inhibitor of Apoptosis (IAPs) and Bcl-2. Furthermore, Bax, a proapoptotic member of the Bcl-2 family, was found to be upregulated in leukemic cell lines treated with greensporone A. Interestingly, gene silencing of AKT using AKT specific siRNA suppressed the expression of Bcl-2 with enhanced expression of Bax. Greensporone A-mediated increase in Bax/Bcl-2 ratio causes permeabilization of the mitochondrial membrane leading to the accumulation of cytochrome c in the cytoplasm. Greensporone A-induced cytochrome c accumulation causes the activation of caspase cascade and cleavage of its effector, poly(ADP-ribose) polymerase (PARP), leading to apoptosis. Greensporone A-mediated apoptosis in leukemic cells occurs through the generation of reactive oxygen species (ROS) due to depletion of glutathione (GSH) levels. Finally, greensporone A potentiated the anticancer activity of imatinib in leukemic cells. In summary, our study showed that greensporone A suppressed the growth of leukemic cells via induction of apoptotic cell death. The apoptotic cell death occurs by inhibition of AKT signaling and activation of the intrinsic apoptotic/caspase pathways. These results raise the possibility that greensporone A could be developed as a therapeutic agent for the treatment of leukemia and other hematological malignancies.

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Meroterpenoids from Neosetophoma sp.: A Dioxa[4.3.3]propellane Ring System, Potent Cytotoxicity, and Prolific Expression

Cited by 47 publications

References 18 publications

Synthetic Biology Driven Biosynthesis of Unnatural Tropolone Sesquiterpenoids

Synthetic Biology Driven Biosynthesis of Unnatural Tropolone Sesquiterpenoids

Synthetisch biologisch getriebene Biosynthese von unnatürlichen Tropolon‐Sesquiterpenoiden

Greensporone A, a Fungal Secondary Metabolite Suppressed Constitutively Activated AKT via ROS Generation and Induced Apoptosis in Leukemic Cell Lines

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