Three Pairs of New Spirocyclic Alkaloid Enantiomers From the Marine-Derived Fungus Eurotium sp. SCSIO F452

Three pairs of new spirocyclic alkaloid enantiomers eurotinoids A–C (1–3), as well as a known biogenetically related racemate dihydrocryptoechinulin D (4) were isolated from a marine-derived fungus Eurotium sp. SCSIO F452. Their structures were determined by spectroscopic analyses and electronic circular dichroism (ECD) calculations. Compounds 1 and 2 represent the first two “meta” products from a non-stereoselective [4 + 2] Diels-Alder cycloaddition presumably between an enone group of a diketopiperazine alkaloid and a diene group of a benzaldehyde derivative via a new head-to-tail coupling mode biosynthetically, while 3 and 4 were “ortho” products. Their enantiomers exhibited different antioxidative and cytotoxic activities. The modes of action were investigated by a preliminary molecular docking study

Engineering the biosynthesis of fungal nonribosomal peptides

Covering: 2011 up to the end of 2021. Fungal nonribosomal peptides (NRPs) and the related polyketide-nonribosomal peptide hybrid products (PK-NRPs) are a prolific source of bioactive compounds, some of which have been developed into essential drugs. The synthesis of these complex natural products (NPs) utilizes nonribosomal peptide synthetases (NRPSs), multidomain megaenzymes that assemble specific peptide products by sequential condensation of amino acids and amino acid-like substances, independent of the ribosome. NRPSs, collaborating polyketide synthase modules, and their associated tailoring enzymes involved in product maturation represent promising targets for NP structure diversification and the generation of small molecule unnatural products (uNPs) with improved or novel bioactivities. Indeed, reprogramming of NRPSs and recruiting of novel tailoring enzymes is the strategy by which nature evolves NRP products. The recent years have witnessed a rapid development in the discovery and identification of novel NRPs and PK-NRPs, and significant advances have also been made towards the engineering of fungal NRP assembly lines to generate uNP peptides. However, the intrinsic complexities of fungal NRP and PK-NRP biosynthesis, and the large size of the NRPSs still present formidable conceptual and technical challenges for the rational and efficient reprogramming of these pathways. This review examines key examples for the successful (and for some less-successful) re-engineering of fungal NRPS assembly lines to inform future efforts towards generating novel, biologically active peptides and PK-NRPs.</p

Microbial transformation of some triterpenoids of Guayule resin by Chaetomium sp.

Microbial biotransformation of argentatin A (1), isoargentatin A (2) and argentatin C (3), the triterpenoid constituents of guayule (Parthenium argentatum) resin was conducted with Chaetomium sp. PA001, an endophytic fungus of the same plant. The experiments yielded six new products (4–9) formed by: (i) nucleophilic oxygenation of the 3-ketone moiety resulting in Baeyer-Villiger oxidation; (ii) lactone ring opening of these oxidation products; (iii) rearrangement of the 9(10)-cyclopropane ring; and (iv) reduction of the 3-ketone moiety. The structures of all new biotransformation products were established by detailed analysis of their spectroscopic data. None of the products exhibited any antimicrobial activity. However, the hydroxy-carboxylic acid derivative 5 of argentatin A showed weak cytotoxic activity, but improved selectivity against human breast cancer cell line MCF-7 compared to the parent compound. This constitutes the first report of microbial biotransformation of isoargentatin A and argentatin C.This project was supported by the USDA-NIFA (grant # 2017- 68005–26867; Dr. Kimberly Ogden, PI) and Hatch Projects 1005072 and 1020652 to A.A.L.G and I.M. Any opinions, findings, conclusions, or recommendations expressed in this publication/work are those of the authors and do not necessarily reflect the view of the U.S. Department of Agriculture. We thank Dr. Lijiang Xuan, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, P. R. China for HRMS data.24 month embargo; first published 16 May 2023This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Diverse Secondary Metabolites from the Coral-Derived Fungus Aspergillus hiratsukae SCSIO 5Bn1003

Three new metabolites, including a cyclic tetrapeptide asperhiratide (1), an ecdysteroid derivative asperhiratine (2), and a sesquiterpene lactone asperhiratone (3), were isolated and identified from the soft coral-derived fungus Aspergillus hiratsukae SCSIO 5Bn1003, together with 10 known compounds. Their structures were elucidated via spectroscopic analysis, X-ray diffraction analysis, and electronic circular dichroism calculations. In addition, the absolute configuration of 1 was determined by Marfey&rsquo;s technique and an analysis of the acid hydrolysates using a chiral phase HPLC column. Among all the compounds, 6 and 8 showed medium cytotoxic activities against four tumor cell lines (SF-268, HepG-2, MCF-7, and A549), with IC50 values ranging from 31.03 &plusmn; 3.04 to 50.25 &plusmn; 0.54 &micro;M. Meanwhile, they strongly inhibited &alpha;-glucosidase activities, with IC50 values of 35.73 &plusmn; 3.94 and 22.00 &plusmn; 2.45 &micro;M, which were close to and even stronger than the positive control acarbose (IC50 = 32.92 &plusmn; 1.03 &micro;M). Compounds 6&ndash;8 showed significant antibacterial activities against Bacillus subtilis, with MIC values of 10.26 &plusmn; 0.76 &micro;M, 17.00 &plusmn; 1.25 &micro;M, and 5.30 &plusmn; 0.29 &micro;M, respectively. Compounds 9 and 12 exhibited potent radical scavenging activities against DPPH, with IC50 values of 12.23 &plusmn; 0.78 &micro;M and 7.38 &plusmn; 1.16 &micro;M. In addition, asperhiratide (1) was evaluated for anti-angiogenic activities in the in vivo zebrafish model, which showed a weak inhibitory effect on intersegmental vessel (ISV) formation

Variecolortins A–C, Three Pairs of Spirocyclic Diketopiperazine Enantiomers from the Marine-Derived Fungus <i>Eurotium</i> sp. SCSIO F452

Three pairs of spirocyclic diketopiperazine enantiomers, variecolortins A–C (<b>1</b>–<b>3</b>), were isolated from marine-derived fungus <i>Eurotium</i> sp. SCSIO F452. Compound <b>1</b> possesses an unprecedented highly functionalized <i>seco</i>-anthronopyranoid carbon skeleton featuring a 2-oxa-7-azabicyclo[3.2.1]­octane core. Compounds <b>2</b> and <b>3</b> represent rare examples of a 6/6/6/6 tetracyclic cyclohexene–anthrone carbon scaffold. Their structures were determined by spectroscopic analyses, X-ray diffraction, and ECD calculations. Their enantiomers exhibited different antioxidative and cytotoxic activities, and their modes of action were investigated

Biosynthesis of Cytosporones in Leotiomycetous Filamentous Fungi

Polyketides with the isochroman-3-one pharmacophore are rare among fungal natural products as their biosynthesis requires an unorthodox S-type aromatic ring cyclization. Genome mining uncovered a conserved gene cluster in select leotiomycetous fungi that encodes the biosynthesis of cytosporones, including isochroman-3-one congeners. Combinatorial biosynthesis in total biosynthetic and biocatalytic formats in Saccharomyces cerevisiae and in vitro reconstitution of key reactions with purified enzymes revealed how cytosporone structural and bioactivity diversity is generated. The S-type acyl dihydroxyphenylacetic acid (ADA) core of cytosporones is assembled by a collaborating polyketide synthase pair. Thioesterase domain-catalyzed transesterification releases ADA esters, some of which are known Nur77 modulators. Alternatively, hydrolytic release allows C6 hydroxylation by a flavin-dependent monooxygenase, yielding a trihydroxybenzene moiety. Reduction of the C9 carbonyl by a short chain dehydrogenase/reductase initiates isochroman-3-one formation, affording cytosporones with cytotoxic and antimicrobial activity. Enoyl di- or trihydroxyphenylacetic acids are generated as shunt products, while isocroman-3,4-diones are formed by autoxidation. The cytosporone pathway offers novel polyketide biosynthetic enzymes for combinatorial synthetic biology to advance the production of “unnatural” natural products for drug discovery