Secalonic Acids Research Articles

Aspergillus derived mycotoxins in food and the environment: Prevalence, detection, and toxicity.

Aspergillus species are the paramount ubiquitous fungi that contaminate various food substrates and produce biochemicals known as mycotoxins. Aflatoxins (AFTs), ochratoxin A (OTA), patulin (PAT), citrinin (CIT), aflatrem (AT), secalonic acids (SA), cyclopiazonic acid (CPA), terrein (TR), sterigmatocystin (ST) and gliotoxin (GT), and other toxins produced by species of Aspergillus plays a major role in food and human health. Mycotoxins exhibited wide range of toxicity to the humans and animal models even at nanomolar (nM) concentration. Consumption of detrimental mycotoxins adulterated foodstuffs affects human and animal health even trace amounts. Bioaerosols consisting of spores and hyphal fragments are active elicitors of bronchial irritation and allergy, and challenging to the public health. Aspergillus is the furthermost predominant environmental contaminant unswervingly defile lives with a 40-90 % mortality risk in patients with conceded immunity. Genomics, proteomics, transcriptomics, and metabolomics approaches useful for mycotoxins' detection which are expensive. Antibody based detection of toxins chemotypes may result in cross-reactivity and uncertainty. Aptamers (APT) are single stranded DNA (ssDNA/RNA), are specifically binds to the target molecules can be generated by systematic evolution of ligands through exponential enrichment (SELEX). APT are fast, sensitive, simple, in-expensive, and field-deployable rapid point of care (POC) detection of toxins, and a better alternative to antibodies.

Ergochromes: Heretofore Neglected Side of Ergot Toxicity.

Ergot, fungal genus Claviceps, are worldwide distributed grass pathogens known for their production of toxic ergot alkaloids (EAs) and the great agricultural impact they have on both cereal crop and farm animal production. EAs are traditionally considered as the only factor responsible for ergot toxicity. Using broad sampling covering 13 ergot species infecting wild or agricultural grasses (including cereals) across Europe, USA, New Zealand, and South Africa we showed that the content of ergochrome pigments were comparable to the content of EAs in sclerotia. While secalonic acids A–C (SAs), the main ergot ergochromes (ECs), are well known toxins, our study is the first to address the question about their contribution to overall ergot toxicity. Based on our and published data, the importance of SAs in acute intoxication seems to be negligible, but the effect of chronic exposure needs to be evaluated. Nevertheless, they have biological activities at doses corresponding to quantities found in natural conditions. Our study highlights the need for a re-evaluation of ergot toxicity mechanisms and further studies of SAs’ impact on livestock production and food safety.

Secalonic Acids J–M, Four New Secondary Metabolites from the Marine-derived Fungus Penicillium oxalicum

Secalonic Acids J–M, Four New Secondary Metabolites from the Marine-derived Fungus Penicillium oxalicum

Evolutionary history of ergot with a new infrageneric classification (Hypocreales: Clavicipitaceae: Claviceps)

The ergot, genus Claviceps, comprises approximately 60 species of specialised ovarial grass parasites famous for the production of food toxins and pharmaceutics. Although the ergot has been known for centuries, its evolution have not been resolved yet. Our approach combining multilocus phylogeny, molecular dating and the study of ecological, morphological and metabolic features shows that Claviceps originated in South America in the Palaeocene on a common ancestor of BEP (subfamilies Bambusoideae, Ehrhartoideae, Pooideae) and PACMAD (subfamilies Panicoideae, Aristidoideae, Chloridoideae, Micrairoideae, Arundinoideae, Danthonioideae) grasses. Four clades described here as sections diverged during the Paleocene and Eocene. Since Claviceps are parasitic fungi with a close relationship with their host plants, their evolution is influenced by interactions with the new hosts, either by the spread to a new continent or the radiation of the host plants. Three of the sections possess very narrow host ranges and biogeographical distributions and have relatively low toxicity. On the contrary, the section Claviceps, comprising the rye ergot, C. purpurea, is unique in all aspects. Fungi in this section of North American origin have spread all over the world and infect grasses in all subfamilies as well as sedges, and it is the only section synthesising toxic ergopeptines and secalonic acids. The evolutionary success of the Claviceps section members can be explained by high toxin presence, serving as feeding deterrents and playing a role in their protective mutualism with host plants. Closely related taxa Neoclaviceps monostipa and Cepsiclava phalaridis were combined into the genus Aciculosporium.

Burchard Franck (1926-2017).

Burchard Frank, Emeritus Professor of Organic Chemistry at the University ofMfnster, passed away on February 21, 2017. He was an internationally recognized natural-product chemist, who made important contributions to the field of biomimetic transformations of alkaloids, as well as the areas of pigments and toxins, and porphyrinoids. Burchard Franck was born on May 6, 1926 in Hamburg. Already in his childhood he came into contact with chemistry, since his father, who earned a PhD in chemistry from the University of Kiel, was a chemistry teacher and later the head of a high school. However, before he could start with his own studies he had to serve in the army at a very young age, and after the end of World War 2, he was a prisoner of war. Finally he commenced his studies in chemistry at the University of Hamburg, which was almost completely destroyed at that time, making his training rather difficult. After completing his diploma with Rudolf Tschesche, he moved to Göttingen, where he received his PhD for work on the red antibiotic rhodomycines carried out under the guidance of Hans Brockmann. The University of Göttingen was one of the few universities that had not been destroyed in the war, and Franck always praised his stay at this school as the most wonderful experience in his life. In 1959 he completed his habilitation with independent work on the biosynthesis of piperidine alkaloids from Sedum acre. Only a few years later, he moved to the University of Kiel. In 1968 he accepted a call to the University of Münster as the successor of Fritz Micheel and Director of the Institute of Organic chemistry, where he remained until his retirement. In between he received offers to move to the Universities of Bonn and Göttingen. A very important tool for Franck's work in the field of biosynthesis was a radionuclide laboratory, and he was able to convince the authorities to provide these rather expensive facilities. A second essential technique was mass spectrometry, for which he always had the newest generation of instruments. Franck's entire scientific career was focused on natural-product chemistry. After his work on piperidine alkaloids, he moved to the tetrahydroisoquinoline alkaloids, where he impressed the community by his outstanding work on biomimetic transformations. He was able to show that alkaloids from the aporphine and morphine type can be obtained from benzyltetrahydroisoquinolines by phenol oxidation after protecting the tertiary nitrogen atom as a quaternary salt. This work, which he presented in a lecture in Freiburg (where I was studying), impressed me so much that I moved to Kiel to become one of his students. Besides alkaloids, another important group of natural products that caught his interest early on were the pigments and toxins of fungi. In 1960, he started working on the ergochromes isolated from Claviceps purpurea and invented a nomenclature for the highly complex dimeric tetrahydroxanthenons (ergochroms, secalonic acids), which is still in use. The compounds were synthesized for the first time only recently. Franck showed that anthraquinones such as emodine are key intermediates in their biosynthesis. Several mycotoxines were also been isolated from fungi and synthesized; in addition their biosynthesis was investigated. In the latter part of his career, Franck moved to the area of porphyrins, where he again performed exciting work. For the investigation of the biosynthesis of these natural products, he carried out an elaborate synthesis to prepare a specifically 14C-labeled [α,γ-14C2]uroporphyrinogen III, and with feeding experiments, he could show that this compound is incorporated into heme without isomerization. Moreover, among other examples, he prepared a hexavinologous porphyrin with an aromatic 30 π system as well as N,N′-bridged porphyrins in a biomimetic fashion. In addition, he synthesized coproporphyrins for photodynamic cancer therapy. Besides his scientific work, Franck was a great teacher and was able to explain chemistry in a very clear and profound way. His lectures were always so perfectly presented that the notes could be used as a textbook. For this reason, he was invited as visiting professor by many universities in the USA, China, and Switzerland. He was a referee for the Deutsche Forschungsgemeinschaft for many years, and he received several awards, including the Richard Kuhn Medal of the Gesellschaft Deutscher Chemiker (GDCh; German Chemical Society) and the Windaus Medal of the University of Göttingen. Burchard Franck, who grew up in the city of Hamburg, was a typical north German with a somewhat reserved character, but he was accepted and greatly respected by his colleagues. He devoted his life to research and teaching and was always supported by his wife Dr. Renate Franck.

Secalonic Acids H and I, Two New Secondary Metabolites from the Marine-Derived Fungus Penicillium oxalicum

Secalonic Acids H and I, Two New Secondary Metabolites from the Marine-Derived Fungus Penicillium oxalicum

Diversity in Secondary Metabolites Including Mycotoxins from Strains of Aspergillus Section Nigri Isolated from Raw Cashew Nuts from Benin, West Africa.

In a previous study, raw cashew kernels were assayed for the fungal contamination focusing on strains belonging to the genus Aspergillus and on aflatoxins producers. These samples showed high contamination with Aspergillus section Nigri species and absence of aflatoxins. To investigate the diversity of secondary metabolites, including mycotoxins, the species of A. section Nigri may produce and thus threaten to contaminate the raw cashew kernels, 150 strains were isolated from cashew samples and assayed for their production of secondary metabolites using liquid chromatography high resolution mass spectrometry (LC-HRMS). Seven species of black Aspergilli were isolated based on morphological and chemical identification: A. tubingensis (44%), A. niger (32%), A. brasiliensis (10%), A. carbonarius (8.7%), A. luchuensis (2.7%), A. aculeatus (2%) and A. aculeatinus (0.7%). From these, 45 metabolites and their isomers were identified. Aurasperone and pyranonigrin A, produced by all species excluding A. aculeatus and A. aculeatinus, were most prevalent and were encountered in 146 (97.3%) and 145 (95.7%) isolates, respectively. Three mycotoxins groups were detected: fumonisins (B2 and B4) (2.7%) ochratoxin A (13.3%), and secalonic acids (2%), indicating that these mycotoxins could occur in raw cashew nuts. Thirty strains of black Aspergilli were randomly sampled for verification of species identity based on sequences of β-tubulin and calmodulin genes. Among them, 27 isolates were positive to the primers used and 11 were identified as A. niger, 7 as A. tubingensis, 6 as A. carbonarius, 2 as A. luchuensis and 1 as A. welwitschiae confirming the species names as based on morphology and chemical features. These strains clustered in 5 clades in A. section Nigri. Chemical profile clustering also showed also 5 groups confirming the species specific metabolites production.

ChemInform Abstract: Asperdichrome, an Unusual Dimer of Tetrahydroxanthone Through an Ether Bond, with Protein Tyrosine Phosphatase 1B Inhibitory Activity, from the Okinawan Freshwater Aspergillus sp. TPU1343.

Abstract A new unusual bis-tetrahydroxanthone connected through an ether bond, named asperdichrome ( 1 ), was isolated from a culture broth of Aspergillus sp. TPU1343 together with two known dimeric polyketides, secalonic acids D ( 2 ) and F ( 3 ). The fungus was isolated from a freshwater sample in Okinawa, Japan. The structure of 1 was elucidated on the basis of its spectroscopic data and comparisons were made with related compounds. Compounds 1 and 3 (heterodimers) inhibited the activity of protein tyrosine phosphatase 1B (PTP1B) with IC 50 values of 6.0 and 9.6 μM, respectively. Compound 2 (homodimer) showed reduced activity against PTP1B (40% inhibition at 15.7 μM). This is the first study on the inhibitory activities of tetrahydroxanthones against PTP1B.

Asperdichrome, an unusual dimer of tetrahydroxanthone through an ether bond, with protein tyrosine phosphatase 1B inhibitory activity, from the Okinawan freshwater Aspergillus sp. TPU1343

A new unusual bis-tetrahydroxanthone connected through an ether bond, named asperdichrome (1), was isolated from a culture broth of Aspergillus sp. TPU1343 together with two known dimeric polyketides, secalonic acids D (2) and F (3). The fungus was isolated from a freshwater sample in Okinawa, Japan. The structure of 1 was elucidated on the basis of its spectroscopic data and comparisons were made with related compounds. Compounds 1 and 3 (heterodimers) inhibited the activity of protein tyrosine phosphatase 1B (PTP1B) with IC50 values of 6.0 and 9.6μM, respectively. Compound 2 (homodimer) showed reduced activity against PTP1B (40% inhibition at 15.7μM). This is the first study on the inhibitory activities of tetrahydroxanthones against PTP1B.

Syntheses of Dimeric Tetrahydroxanthones with Varied Linkages: Investigation of "Shapeshifting" Properties.

The 2,4'- and 4,4'-linked variants of the cytotoxic agent secalonic acid A and their analogues have been synthesized. Kinetic resolution of an unprotected tetrahydroxanthone scaffold followed by copper-mediated biaryl coupling allowed for efficient access to these compounds. Evaluation of the "shapeshifting" properties of 2,2'-, 2,4'-, and 4,4'-linked variants of the secalonic acids A in a polar solvent in conjunction with assays of the compounds against select cancer cell lines was conducted to study possible correlations between linkage variation and cytotoxicity.

Stannylation and Stille Coupling of Base‐Sensitive Tetrahydroxanthones to Heteromeric Biaryls

AbstractHerein, the synthesis of heteromeric tetrahydroxanthone biaryls is described, a widespread core structure of many natural products. The development of both stannylation and Stille coupling procedures of base‐sensitive tetrahydroxanthones enabled their coupling with benzene derivatives as well as with xanthenes. These methods provide access to structures that are analogous to parnafungins as well as to dimeric compounds similar to secalonic acids or phomoxanthones.magnified image

Parmeliaceae family: phytochemistry, pharmacological potential and phylogenetic features

Parmeliaceae is the largest family of lichenized fungi comprising about 2700 species distributed in about 80 genera. A wide array of secondary metabolites including depsides, depsidones, aliphatic acids, triterpenes, anthraquinones, secalonic acids, pulvinic acid derivatives and xanthones have been identified within this family. Many of these bioactive compounds such as usnic acid and atranorin are exclusively found in this family, being of great relevance for the systematics and phylogeny. Moreover, these compounds exert different biological roles including antimicrobial, antioxidant, cytotoxic, anti-inflammatory, analgesic and enzyme inhibitory actions. The current review focuses on the phytochemistry and main phylogenetic aspects of Parmeliaceae, and it discusses the pharmacological findings and mechanisms of action of their extracts and isolated compounds. The present work actually collects information related to more than 65 lichen species (from 21 different genuses and heterogeneous distribution) and 75 isolated metabolites. As reported, the best studied genus from a pharmacological point of view is Parmelia, followed by Usnea. At the species level, Cetraria islandica and Evernia prunastri attract remarkable interest in their bioactive activities and metabolite content. The major pharmacological activities investigated on extracts and compounds from Parmeliaceae spp. have been antimicrobial, anticancer and antioxidant potentials; and regarding isolated compounds, the aforementioned usnic acid and atranorin are among the most studied metabolites. Reviewed data suggest that some of these lichens and natural compounds are worthy of further investigation.

ChemInform Abstract: Total Syntheses of Secalonic Acids A and D.

Total syntheses of the dimeric tetrahydroxanthone natural products secalonic acids A and D are described. Key steps involve kinetic resolution of the tetrahydroxanthone core structure using homobenzotetramisole catalysis and late-stage copper(I)-mediated homodimerization of complex aryl stannane monomers.

Dereplication guided discovery of secondary metabolites of mixed biosynthetic origin from Aspergillus aculeatus.

Investigation of the chemical profile of the industrially important black filamentous fungus Aspergillus aculeatus by UHPLC-DAD-HRMS and subsequent dereplication has led to the discovery of several novel compounds. Isolation and extensive 1D and 2D NMR spectroscopic analyses allowed for structural elucidation of a dioxomorpholine, a unique okaramine, an aflavinine and three novel structures of mixed biosynthetic origin, which we have named aculenes A–C. Moreover, known analogues of calbistrins, okaramines and secalonic acids were detected. All novel compounds were tested for antifungal activity against Candida albicans, however all showed only weak or no activity. Aspergillus aculeatus IBT 21030 was additionally shown to be capable of producing sclerotia. Examination of the sclerotia revealed a highly regulated production of metabolites in these morphological structures.

Double Trouble—The Art of Synthesis of Chiral Dimeric Natural Products

Double or nothing! Recently the total synthesis of secalonic acids A and D was reported. This work and other natural product syntheses with a dimerization step as a common feature are featured in this Highlight. The significant biological activity of the secalonic acids and the fact that their synthesis has fascinated synthetic chemists for the past forty years make this work a milestone in natural product synthesis.

Total syntheses of secalonic acids A and D.

Total syntheses of the dimeric tetrahydroxanthone natural products secalonic acids A and D are described. Key steps involve kinetic resolution of the tetrahydroxanthone core structure using homobenzotetramisole catalysis and late-stage copper(I)-mediated homodimerization of complex aryl stannane monomers.

Total Syntheses of Secalonic Acids A and D

AbstractTotal syntheses of the dimeric tetrahydroxanthone natural products secalonic acids A and D are described. Key steps involve kinetic resolution of the tetrahydroxanthone core structure using homobenzotetramisole catalysis and late‐stage copper(I)‐mediated homodimerization of complex aryl stannane monomers.

Cyclodepsipeptides, α-Pyrone Derivatives and Secalonic Acids from Two Unidentified Freshwater Fungi (G100 and G102)

The chemical mycology of freshwater fungi is practically uninvestigated. In ongoing studies to explore fungi (Ascomycota) from freshwater habitats in North Carolina, eight compounds were isolated from organic extracts of two unidentified freshwater fungi (G100 and G102). Of these, two were cyclodepsipeptides [Sch 378161 (1) and Sch 217048 (3)], two belong to the secalonic acid family, the known dimeric [secalonic acid A (3)] and a new monomer [8,8a-dihydroerogchrome A (4)], and four α-pyrone derivatives, two known [phomopsinone A (5) and phomopsinone D (6)] and two new [phomopsinone E (7) and phomopsinone F (8)]. The structures of the isolated compounds were elucidated using a set of spectroscopic and spectrometric techniques (HRESIMS and 1H, 13C, COSY, HSQC, HMBC, and NOESY NMR). The biological activities of these classes of compounds suggest that they afford a competitive advantage to the fungi.

UV-protectant metabolites from lichens and their symbiotic partners

Lichens are structurally complex symbiotic organisms that are exposed to a wide variety of external conditions (extreme temperatures, desiccation, UV radiation, etc.). These poikilohydric organisms have developed various mechanisms of photoprotection, such as light scattering, radiation screening, thermal dissipation, activation of antioxidant defense and macromolecules and membrane repair. These unique organisms produce a vast array of compounds, with more than 1000 secondary metabolites known. An important protective mechanism of lichens is the production of UV screening compounds, such as phenolic compounds (depsidones, depsides, diphenyl ethers), anthraquinones, xanthones or shikimic acid derivatives (calycin, mycosporines, scytonemin). Due to the harmful effects of the UVA wavelengths of sunlight, the search for new sunscreens remains important. We herein propose a review that focuses on the UV protectants from lichens and their symbiotic partners (lichenized fungi, green alga, cyanobacteria). In fact, lichens produce unique and/or efficient UV filters such as depsidones (lobaric acid, pannarin, etc.), depsides (atranorin, gyrophoric acid, etc.), diphenyl ethers (epiphorellic acids, buellin), bisxanthones (secalonic acids, etc.), mycosporines and MAAs, scytonemin along with classical pigments (melanin, carotenoids). We propose to classify these compounds with regard to their chemical structures and review the physicochemical properties that act as UV filters. While the most abundant lichen polyfunctionalized aromatic compounds, belonging to orsellinic derivatives, are UVB screens, these organisms produce strong UVA filters, e.g., calycin (pulvinic acid derivatives), bisxanthones (secalonic acids), scytonemin or mycosporines and MAAs with the latter ones exhibiting attractive properties as photoprotectants.

Cytotoxic Constituents of the Lichen Diploicia canescens

A new diphenyl ether (1), along with 12 known compounds, was isolated from the lichen Diploicia canescens. The structure of compound 1 was elucidated by spectroscopic data analysis, and the biosynthetic origin of this product is discussed. Secalonic acids B (7), D (8), and F (9) were isolated for the first time from D. canescens. The cytotoxic activities of 1-3, 6-8, and 10 against the B16 murine melanoma and HaCaT human keratinocyte cell lines were evaluated.